N-heterocyclic compounds and methods of use thereof

Abstract

The application provides novel N-heterocyclic compounds, such as quinoline or isoquinoline compounds, preferably quinazoline compounds, as calcineurin inhibitors (CNIs,) that provide improved safety profiles, and the pharmaceutical composition and formulation thereof, as well as a method of using the N-heterocyclic compounds for the treatment of, inter alia, an inflammatory-related disease or disorder.

Description

RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 63 / 624,563, filed on January 24, 2024. The entire teachings of the above application are incorporated herein by reference. FIELD OF THE APPLICATION This application relates to new compositions of biologically active compounds that are useful for treating diseases and methods of making such compositions. BACKGROUND Inflammatory-related diseases and disorders represent a significant healthcare challenge, impacting the well-being of individuals across the globe. These conditions encompass a broad spectrum of ailments, ranging from pulmonary' disorders to skin conditions, and ocular diseases. Calcineurin plays a pivotal role in the immune system and the pathogenesis of inflammatory-related diseases and disorders. It serves as a crucial catalyst in T-cell activation by promoting the activation of Nuclear Factor of Activated T-cells (NF AT), consequently leading to the upregulation of interleukin 2 (IL-2) and the fostering of T-cell growth and differentiation in immune responses. As a result, calcineurin has emerged as a primary target for immunosuppressive drugs, which include cyclosporine, voclosporin, pimecrolimus, and tacrolimus. Nevertheless, these calcineurin inhibitors (CNIs) are associated with a range of potential side effects, such as elevated blood pressure, renal complications, an increased susceptibility to infections, and in the case of topical applications like pimecrolimus and tacrolimus, localized skin irritation. Also, CNIs have been a cornerstone in the immunosuppressive regimens for organ transplantation, notably exemplified by tacrolimus for kidney transplant. Lentine et al., “OPTNSRTR 2021 Annual Data Report: Kidney"', American Journal of Transplantation, Volume 23, Issue 2, Supplement 1, 2023, Pages S21-S120, ISSN 1600-6135. https: / / doi.Org / 10.1016 / j.ajt.2023.02.004. However, the standard of care for CNIs has been associated with several areas of safety concern, notably impacting renal function, blood pressure, glucose tolerance, hyperlipidemia, and neurotoxicity. One of the predominant challenges associated with CNI therapy, particularly tacrolimus, is nephrotoxicity. Despite advancements in patient selection and dosing strategies, nephrotoxicity remains a significant concern, often necessitating substantial dose reduction or discontinuation of CNIs. The impact on renal function not only poses a clinical challenge but also contributes to patient nonadherence, reflecting a key dose-limiting issue for tacrolimus. Naesens et al., "Calcineurin inhibitor nephrotoxicity". Clinical Journal of the American Society of Nephrology. (February 2009) 4 (2): 481-508. Another major concern is tacrolimus-induced CNS toxicity, with common side effects such as headache, insomnia, and tremor. More severe manifestations, including psychosis, visual changes, and seizures, further compound the challenges associated with this class of immunosuppressants. The cumulative impact of these side effects on patient compliance is profound. Nonadherence rates have surged, reaching up to 65% in young adults and a notable increase from 17% at baseline to 31% at 18% post-transplantation in adult kidney transplant recipients. This trend underscores the imperative need for novel CNIs that provide improved safety profiles and enhance patient adherence to post-transplantation regimens. SUMMARY OF THE INVENTION The invention is based on the discovery of the unexpected therapeutic effect of a novel compound on treating inflammatory-related diseases and disorders. The compound comprises a core N-heterocyclic moiety and is represented by Formula (I): Formula (I), wherein all the variables are as defined below. Provided are also a method for treating inflammatory-related diseases and disorders including pulmonary, skin, or ocular conditions: a method for preventing organ transplant rejection; and a method of treating fungal infection. DETAILED DESCRIPTION Compounds The compounds of the invention comprise a nitrogen-containing bicyclic heteroaromatic system (such as a quinoline, or an isoquinoline or a quinazoline moiety). The compounds of the invention can be represented by Formula (I): Formula© or a pharmaceutically acceptable salt, a stereoisomer and a mixture of stereoisomers, or a prodrug thereof; wherein each Ri, R2, and R3 is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SOsRa, COORa, C(O)Ra, and C(O)NRbRc; R4 is selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl. substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(0)Ra, and C(O)NRbRc; each Ra, Rb, and Rc is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or Rb and Rc can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring; Rs and Re together form a substituted or unsubstituted a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; wherein the substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally fused or optionally bridged; Xi and X2 are each independently selected from -0- or -NRb-; Yi and Y2 are independently selected from CH and N. provided that at least one of Yi and Y2 is N; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and 0 is 0, 1, 2, 3. or 4. In some cases, Y1 represents N and Y2 represents CH. In some cases, Yi represents CH and Y2 represents N. In some cases, Y1 represents N and Y2 represents N. In some embodiments, Xi and X2 are each independently selected from -O- or -NRb-, wherein Rb is H, D, a substituted or unsubstituted C1-6 alkyl. In some cases, Xi and X2 are each independently selected from -0- or -NRb-. wherein Rb is H or -CH3. In some cases, both Xi and X2 are -0-. In some cases, both Xi and X2 are -NH-. In some cases, one of Xi and X2 is -0- and the other is -NH-. Preferred compounds of the invention comprise a quinazoline moiety, wherein Y1 represents N and Y2 represents N, resulting in Formula (II): R6-'Z Formula (II), or a pharmaceutically acceptable salt, a stereoisomer and a mixture of stereoisomers, or a prodrug thereof; wherein each variable is as defined above, including all additional and preferred embodiments. In some embodiments, each Ri, R2, and R3 is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(O)Ra, and C(O)NRbRc; R4 is selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(O)Ra, and C(O)NRbRc; each Ra, Rb, and Rc is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or Rb and Rc can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring; R5 and Re together form a substituted or unsubstituted a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; wherein the substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally fused or optionally bridged; Xi and X2 are each independently selected from -0- or -NRb-; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and 0 is 0, 1, 2, 3. or 4. In some embodiments, Xi and X2 are each independently selected from -O- or -NRb-, wherein Rb is H, D, a substituted or unsubstituted C1-6 alkyl. In some cases, Xi and X2 are each independently selected from -O- or -NRb-, wherein Rb is H or -CH3. In some cases, both Xi and X2 are -0-. In some cases, both Xi and X2 are -NH-. In some cases, one of Xi and X2 is -0- and the other is -NH-. In some embodiments, both Xi and X2 are -0-, resulting in Formula (III): Formula (III), Wherein the variables Ri, R2, R3, R4, Rs. Re, m, n, and 0 are as defined above, including all preferred and additional embodiments. In some embodiments, m is 1, 2, 3, 4, or 5; or m is 2, 3, 4, or 5; or m is 3, 4, or 5. In some preferred embodiment, m is 4 or 5. In some more preferred embodiments, m is 5. In some embodiments, each Ri, R2, R3, R4 is independently selected from a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alkyl, OH, F, Cl, Br. CN, -CONHRb, COORa; wherein each Ra is independently H or a substituted or unsubstituted Ci-6 alkyl, each Rb is independently H, OH, or a substituted or unsubstituted Ci-6 alkyl. The preferred substituents include F, Cl. Br; preferably F. Preferably, each Ri is independently F, Cl, Br, a substituted or unsubstituted C1-3 alkyl, a substituted or unsubstituted -O-C1-3 alkyl, or a substituted or unsubstituted -COO-C1-3 alkyl. Preferably, each Ri is independently -CH3, -CH2CH3, -OCH3. -OCH2CH3, or -COOH. In some cases, at least one Ri is -COOH. In some cases, one Ri is -COOH. In some cases, at least one Ri is -CH3 or -CH2CH3. In some cases, at least two Ri are each independently selected from -CH3 or -CH2CH3. In some cases, at least three Ri are each independently selected from -CH3 or -CH2CH3. In some cases, four Ri are each independently selected from -CH3 or -CH2CH3. In some embodiments, m is 1, 2, 3, 4, or 5; the Ri attached to the phenyl ring at the para position (or the 4 position) with regard to the ether bond is -COORa, resulting in Formula (IV): Formula (IV). Wherein the variables Ri, R2, R3, R4, Rs. Re. m, n. and 0 are as defined above, including all preferred and additional embodiments; and R7 is H, D, or a substituted or unsubstituted alkyl (preferably a substituted or unsubstituted Ci-e alkyl). Preferably, R7 is H, Formula (IV) is therefore further represented by the formula as shown below: In some embodiments, with reference to any of the formulas above. Rs and Re together form a ring structure, the structure of R4 / R5 / R6 includes: wherein each of the ring groups above is substituted with zero, one, two, three, four, or five substituents selected from -OH, a C1-3 alkyl, a -O-C1-3 alkyl, -CN, and =O. In some embodiments, with reference to Formula (II), Rs and Rs form a substituted or unsubstituted 2,5-cyclohexadienone. which is substituted with zero, one, two, three, four, or five substituents, resulting in Formula (V): Formula (V), Wherein the variables Ri, R2, R3, R4, Xi, and X2, m, n, and 0 are as defined above, including all preferred and additional embodiments; Rs is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, CN, NRbRc, NRaC(O)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SOsRa, COORa, C(O)Ra, and C(0)NRbRc; Ra, Rb, and Rc are as defined above; p is 0, 1, 2, 3. or 4. In some embodiments, Rs is H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(O)Ra, and C(O)NRbRc. In some embodiments, with reference to Formula (V). Xi and X2 are both -0-, resulting in Formula (VI): Formula (VI). wherein the variables Ri, R2, R3, R4, Rs, m, n, 0, and p are as defined above, including all preferred and additional embodiments. In some embodiments, with reference to Formula (VI), the Ri attached to the phenyl ring at the para position (or the 4 position) with regard to the ether bond is -COORa, resulting in Formula (VII): Formula (VII), Wherein the variables Ri, R2, R3, R4, R7. Rs, m, n, o, and p are as defined above, including all preferred and additional embodiments. With reference to any one of the formulas above, in some embodiments, n is 1, 2, or 3; preferably n is 2. Preferably, each R2 and each R3 is independently selected from F, Cl, Br, OH, a -0-C1-3 alkyl such as -OCH3, a substituted or unsubstituted C1-3 alkyl such as -CH3, -CF3, or -CH2CH3. Preferably, each R2 is independently -CH3 or -CH2CH3. Preferably, n is 2, and both R2 are -CH3. In some embodiments, 0 is 1, 2, 3, or 4; or 0 is 2, 3, or 4; or 0 is 3 or 4; preferably 0 is 4. In some cases, 0 is 4; at least one R3 is OH. In some cases, 0 is 4; at least one R3 is F, Cl, or Br. In some cases, 0 is 4; at least one R3 is OH, and at least one R3 is F, Cl, or Br. In some cases, 0 is 4; at least one R3 is -CHs or -CH2CH3; or at least two Ra are each independently -CH3 or -CH2CH3; or at least three R3 are each independently -CH3 or -CH2CH3; or four R3 are each independently -CH3 or -CH2CH3. In some cases, each R3 is -CH3. In some embodiments, R4 is OH, -NH2, F, Cl, a substituted or unsubstituted C1-6 alkyd (preferably, -CH3 or -CH2CH3). Preferably, R4 is OH. With reference to any one of Formulas (V)-(VII), p is preferably 1, 2. or 3. More preferably, p is 2. In some embodiments, each Rs is independently7 selected from a substituted or unsubstituted C1-6 alky l, a substituted or unsubstituted -O-C1-6 alkyl, F, Cl, Br, OH, CN, -CONHRb, COORa; each Ra is independently H or a substituted or unsubstituted C1-6 alkyl, and each Rb is independently H. OH, or a substituted or unsubstituted C1-6 alkyl. Preferably, each Rs is independently selected from a substituted or unsubstituted C1-3 alkyl, and a substituted or unsubstituted -O-C1-3 alkyl. In some cases, each Rs is independently selected from -CH3, -CH2CH3, -OCH3. and -OCH2CH3. In some cases, p is 2, both Rs are -CH3. In some cases, p is 2, one Rs is -CHs and the other Rs is -OCH3. In additional embodiments, with reference to any one of the formulas above wherein they are present, one or more of Ri, R2, Rs, R4, or Rs is independently a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- to 6-membered heteroaryl, a substituted or unsubstituted 3- to 6-membered cycloalkyl, or a substituted or unsubstituted 3-to 6-membered heterocycloalky7!, including but not limited to: wherein each of the groups above is substituted with zero, one, two, three, or four substituents. Non-limiting exemplary compounds are summarized in Table 1 Table 1. Exemplary compounds of the invention #          Compound Structure 28                  Br MeCT^^O 29                   Br MeCr^X) Each preferred embodiment described herein can be taken in combination with one, any or all other preferred embodiments, as though presented herein in every permutation. Compositions of the invention can comprise racemic mixtures, pure enantiomers, or an excess of one enantiomer over the other. For example, a composition can comprise an enantiomeric excess of at least 5, 10, 20, 30, 40, 50, 60, 70, 80 or 90%. In one embodiment, the enantiomeric excess is at least 95%. The compounds of the invention include all enantiomers which may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, as well as their racemic and optically pure forms, and is not limited to those described herein in any of their pharmaceutically acceptable forms, including enantiomers, salts, solvates, polymorphs, solvatomorphs, hydrates, anhydrous and other crystalline forms and combinations thereof. Likewise, all tautomeric forms are intended to be included. Preferably, a pharmaceutical composition comprises a compound of the invention as an R enantiomer in substantially pure form; or, a pharmaceutical composition comprises a compound of the invention as an S enantiomer in substantially pure form; or, a pharmaceutical composition comprises a compound of the invention as enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer. It is particularly preferred that the pharmaceutical composition contains a compound of the invention which is a substantially pure optical isomer. For the avoidance of doubt, a compound of the invention can, if desired, be used in the form of solvates. In some embodiments, the compound of the invention is synthesized following synthetic procedures analogous to Scheme (I): Scheme (I). The R groups in Scheme (I) respectively adopt the definitions of Ri, R2, R3, Rs at the corresponding positions, including all preferred and additional embodiments. In some embodiments, the compounds of the invention are synthesized following synthetic procedures analogous to the schemes as shown below and / or further described in the Examples section. An exemplary synthetic scheme of Example 15 is provided below: 1) Pd(OAc)2 (20 mol %) BINAP (40 mol %) Cs2CO3 (3 Equiv.) Ph2C=NH (2 Equiv.) BnBr (1.05 Equiv.) K2CO3 (1.2 Equiv) Tf2O (1.5 Equiv.) Pyridine (5 Equiv.) H2N xNH 4 Equiv. POCI3 (60 Equiv.) 2) HOI 1 Equiv. C^COs (1.1 Equiv.) HCI (50 Equiv.) HO An exemplary' synthetic scheme of Example 19 is provided below: PinB^QEt 1 Equiv. Pd(PPh3)4(10 mol %) K2CO3 (3 Equiv.) HCL An exemplary' synthetic scheme of Example 15 and Example 16 are provided below: Example 16 Example 17 An exemplary' synthetic scheme of Example 29 is provided below: VinyIBpin, [Pd] DIPEA (1V) POCI3(10V) Toluene, 110 °C, 4h Cs2CO3, DMF, 60 °C, 4h H2 (1 atm) Pd / C THF, 25 °C, 1h BOP-CI (1.2 equiv.), NEt3 (5 equiv.) DMAP (0.1 equiv.) DCM, 1h, 25 °C Formulation of Compositions The administration of the compounds of the invention may be by any suitable means that results in the reduction of perceived pain sensation at the target region. The compounds of the invention may be contained in any appropriate amount in any suitable carrier substance and are generally present in amounts totaling 1 -99% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intrathecal, epidural, or ocular administration, or by injection, inhalation, or direct contact with the nasal or oral mucosa. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 22nd edition, 2013, ed. L.V. Allen, Pharmaceutical Press, Philadelphia, and Encyclopedia of Pharmaceutical Technology, 4th Edition, ed. J. Swarbrick. 2013, CRC Press, New York). Each compound may be formulated in a variety of ways that are known in the art. For example, a compound of the invention and a biologically active agent as defined herein may be formulated together or separately. Desirably, a compound of the invention and a biologically active agent are formulated together for their simultaneous or near simultaneous administration. In another embodiment, two or more biologically active agents may be formulated together with a compound of the invention, or separately. Other examples include, but are not limited to, two or more compounds of the invention formulated together, wherein the compounds are formulated together with or without one or more biologically active agents. The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include but are not limited to kits that contain, e.g.. two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like. Controlled Release Formulations Each compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be formulated for controlled release (e.g., sustained or measured) administration, as described in U.S. Patent Application Publication Nos. 2003 / 0152637 and 2005 / 0025765, each incorporated herein by reference. For example, a compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be incorporated into a capsule or tablet that is administered to the patient. Any pharmaceutically acceptable vehicle or formulation suitable for local application and / or injection into a site to be treated (e.g., a painful surgical incision, wound, or joint), that is able to provide a sustained release of compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, may be employed to provide for prolonged elimination or alleviation of inflammation, as needed. Controlled release formulations known in the art include specially coated pellets, polymer formulations or matrices for surgical insertion or as sustained release microparticles, e.g., microspheres or microcapsules, for implantation, insertion, infusion or injection, wherein the slow release of the active medicament is brought about through sustained or controlled diffusion out of the matrix and / or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix. Other formulations or vehicles for controlled, sustained or immediate delivery7 of an agent to a preferred localized site in a patient include, e.g., suspensions, emulsions, gels, liposomes and any other suitable art known delivery vehicle or formulation acceptable for subcutaneous or intramuscular administration. A wide variety of biocompatible materials may be utilized as a controlled release carrier to provide the controlled release of a compound of the invention, alone or in combination with one or more biologically active agents, as described herein. Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art may be utilized. It is preferred that the biocompatible controlled release material degrade in vivo within about one year, preferably within about 3 months, more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50% of the material degrading into non-toxic residues, which are removed by the body, and 100% of the compound of the invention being released within a time period within about two weeks, preferably within about 2 days to about 7 days. A degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local antinociceptive effect over the desired time period. Suitable biocompatible polymers can be utilized as the controlled release material. The polymeric material may comprise biocompatible, biodegradable polymers, and in certain preferred embodiments, is preferably a copolymer of lactic and glycolic acid. Preferred controlled release materials which are useful in the formulations of the invention include the poly anhydrides, polyesters, co-polymers of lactic acid and glycolic acid (preferably wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 i.e.. 80% or less lactic acid to 20% or more glycolic acid by weight) and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride. Examples of polyesters include polylactic acid, poly glycolic acid and polylactic acid-polyglycolic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen and polysaccharides such as hyaluronic acid. The polymeric material may be prepared by any method known to those skilled in the art. For example, where the polymeric material is comprised of a copolymer of lactic and glycolic acid, this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539, incorporated herein by reference. Alternatively, copolymers of lactic and glycolic acid may be prepared by any other procedure known to those skilled in the art. Other useful polymers include polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters or mixtures or blends of any of these. Pharmaceutically acceptable poly anhydrides which are useful in the present invention have a water-labile anhydride linkage. The rate of drug release can be controlled by the particular polyanhydride polymer utilized and its molecular weight. The polysaccharides may be poly-l,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof. The biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-1.4-glucan, including hydrolyzed amylopectin, derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. The polyanhydride polymer may be branched or linear. Examples of poly mers which are useful in the present invention include (in addition to homopolymers and copolymers of poly(lactic acid) and / or poly(glycolic acid)) poly[bis(p-carboxyphenoxy) propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated aliphatic acids, polyanhydride polymers prepared from amino acids which are modified to include an additional carboxylic acid, aromatic polyanhydride compositions, and co-polymers of polyanhydrides with other substances, such as fatty acid terminated polyanhydrides, e.g., polyanhydrides polymerized from monomers of dimers and / or trimers of unsaturated fatty acids or unsaturated aliphatic acids. Polyanhydrides may be prepared in accordance with the methods set forth in U.S. Pat. No. 4,757,128, incorporated herein by reference. Poly orthoester polymers may be prepared, e.g., as set forth in U.S. Pat. No. 4,070,347, incorporated herein by reference. Polyphosphoesters may be prepared and used as set forth in U.S. Pat. Nos. 6,008,318, 6,153,212, 5.952,451, 6,051.576, 6,103.255, 5,176,907 and 5.194,581, each of which is incorporated herein by reference. Proteinaceous polymers may also be used. Proteinaceous polymers and their soluble derivatives include gelation biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like. Biodegradable synthetic polypeptides include poly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine, copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine. and the like. In additional embodiments, the controlled release material, which in effect acts as a carrier for a compound of the invention, alone or in combination with one or more biologically active agents as described herein, can further include a bioadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or nontoxic lectins or the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan. In embodiments where the biodegradable polymer comprises a gel, one such useful polymer is a thermally gelling polymer, e.g., polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127 from BASF Wyandotte. In such cases, the local anesthetic formulation may be injected via syringe as a free-flowing liquid, which gels rapidly above 30° C. (e.g., when injected into a patient). The gel system then releases a steady dose of a compound of the invention, alone or in combination with one or more biologically active agents as described herein, at the site of administration. Dosage Forms for Oral Use Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, taste masking agents (such as hydroxypropyl methylcellulose, hydroxypropyl cellulose), and the like. One or more compounds of the invention and one or more biologically active agents, as defined herein, may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, a compound of the invention is contained on the inside of the tablet, and the biologically active agent is on the outside of the tablet, such that a substantial portion of the biologically active agent is released prior to the release of the compound of the invention. Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g.. a mixer, a fluid bed apparatus or a spray drying equipment. Formulations for oral administration to the mouth may also be provided as a mouthwash, an oral spray, oral rinse solution, oral ointment, or oral gel. Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and / or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Generally, when administered to a human, the oral dosage of any of the compounds of the combination of the invention will depend on the nature of the compound, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be necessary. Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. Parenteral Formulations Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection. Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng / ml to about 10 pg / ml, for example from about 10 ng / ml to about 1 pg / ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Topical Formulations The compositions of the invention, alone or in combination with one or more of the biologically active agents described herein, can also be adapted for topical use with a topical vehicle containing from between 0.0001% and 25% (w / w) or more of active ingredient(s). In a preferred combination, the active ingredients are preferably each from between 0.0001% to 10% (w / w), more preferably from between 0.0005% to 4% (w / w) active agent. The topical formulation, including but not limited to a cream, gel, or ointment, can be applied one to four times daily, or as needed. Performing the methods described herein, the topical vehicle containing the composition of the invention, or a combination therapy containing a composition of the invention is preferably applied to the site of inflammation on the patient. For example, a cream may be applied to the hands of a patient suffering from arthritic fingers. The compositions can be formulated using any dermatologically acceptable carrier. Exemplary7 carriers include a solid carrier, such as alumina, clay, microciystalline cellulose, silica, or talc; and / or a liquid carrier, such as an alcohol, a glycol, or a water-alcohol / glycol blend. The therapeutic agents may also be administered in liposomal formulations that allow therapeutic agents to enter the skin. Such liposomal formulations are described in U.S. Pat. Nos. 5,169,637; 5,000,958; 5,049,388; 4,975,282; 5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704; 5,552,155; 5,356,633; 5,032,582; 4,994,213; 8,822,537, and PCT Publication No. WO 96 / 40061. Examples of other appropriate vehicles are described in U.S. Pat. Nos. 4,877,805, 8.822,537, and EP Publication No. 0586106A1. Suitable vehicles of the invention may also include mineral oil, petrolatum, poly decene, stearic acid, isopropyl myristate, polyoxyl 40 stearate, stearyl alcohol, or vegetable oil. The composition can further include a skin penetrating enhancer, such as those described in "‘Percutaneous Penetration enhancers7’, (eds. Smith E W and Maibach H I. CRC Press 1995). Exemplary skin penetrating enhancers include alkyl (N,N-disubstituted amino alkanoate) esters, such as dodecyl 2-(N,N dimethylamino) propionate (DDAIP), which is described in patents U.S. Pat. Nos. 6,083,996 and 6,118,020, which are both incorporated herein by reference; a water-dispersible acid polymer, such as a polyacrylic acid polymer, a carbomer (e.g., Carbopol™ or Carbopol 940P™, available from B. F. Goodrich Company (Akron, Ohio)), copolymers of polyacrylic acid (e.g., Pemulen™ from B. F. Goodrich Company or Polycarbophil™ from A. H. Robbins, Richmond, Va.; a polysaccharide gum, such as agar gum, alginate, carrageenan gum, ghatti gum, karaya gum, kadaya gum, rhamsan gum. xanthan gum, and galactomannan gum (e.g.. guar gum, carob gum, and locust bean gum), as well as other gums known in the art (see for instance, Industrial Gums: Polysaccharides & Their Derivatives, Whistler R. L., BeMiller J. N. (eds.). 3rd Ed. Academic Press (1992) and Davidson, R. L., Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980)); or combinations thereof. Other suitable polymeric skin penetrating enhancers are cellulose derivatives, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose. Additionally, known transdermal penetrating enhancers can also be added, if desired. Illustrative are dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA), 2-pyrrolidone, N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptane-2-one (Azone™, a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium thioglycolate and other enhancers such as dioxolanes, cyclic ketones, and their derivatives and so on. Also illustrative are a group of biodegradable absorption enhancers which are alkyl N,N-2-(disubstituted amino) alkanoates as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866, which are both incorporated herein by reference, including: tetradecyl (N,N-dimethylamino) acetate, dodecyl (N.N-dimethylamino) acetate, decyl (N.N-dimethylamino) acetate, octyl (N,N-dimethylamino) acetate, and dodecyl (N,N-diethylamino) acetate. Particularly preferred skin penetrating enhancers include isopropyl myristate; isopropyl palmitate; dimethyl sulfoxide; decyl methyl sulfoxide; dimethylalanine amide of a medium chain fatty’ acid; dodecyl 2-(N,N-dimethylamino) propionate or salts thereof, such as its organic (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acid addition salts) and inorganic salts (e.g., acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfamic, picric, and lactic acid addition salts), as described in U.S. Pat. No. 6,118,020; and alkyl 2-(N,N-disubstituted amino)-alkanoates. as described in U.S. Pat. No. 4,980,378 and U.S. Pat. No. 5,082,866. The skin penetrating enhancer in this composition by weight would be in the range of 0.5% to 10% (w / w). The most preferred range would be between 1.0% and 5% (w / w). In another embodiment, the skin penetrating enhancer comprises between 0.5%-l%, l%-2%, 2%-3%, 3%-4%, or 4%-5%, (w / w) of the composition. The compositions can be provided in any useful form. For example, the compositions of the invention may be formulated as solutions, emulsions (including microemulsions), suspensions, creams, ointments, foams, lotions, gels, powders, or other ty pical solid, semisolid. or liquid compositions (e.g., topical sprays) used for application to the skin or other tissues where the compositions may be used. Such compositions may contain other ingredients typically used in such products, such as colorants, fragrances, thickeners (e.g., xanthan gum, a fatty acid, a fatty acid salt or ester, a fatty alcohol, a modified cellulose, a modified mineral material, Krisgel 100™, or a synthetic polymer), antimicrobials, solvents, surfactants, detergents, gelling agents, antioxidants, fillers, dyestuffs, viscosity-controlling agents, preservatives, humectants, emollients (e g., natural or synthetic oils, hydrocarbon oils, waxes, or silicones), hydration agents, chelating agents, demulcents, solubilizing excipients, adjuvants, dispersants, skin penetrating enhancers, plasticizing agents, preservatives, stabilizers, demulsifiers, wetting agents, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and optionally including anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals. The compositions can also include other like ingredients to provide additional benefits and improve the feel and / or appearance of the topical formulation. Specific classes of additives commonly use in these formulations include: isopropyl myristate, sorbic acid NF powder, polyethylene glycol, phosphatidylcholine (including mixtures of phosphatidylcholine, such as phospholipon G), Krisgel 100™ distilled water, sodium hydroxide, decyl methyl sulfoxide (as a skin penetrating enhancer), menthol crystals, lavender oil, butylated hydroxy toluene, ethyl diglycol reagent, and 95% percent (190 proof) ethanol. Formulations for Ophthalmic Administration The compounds of the invention can also be formulated with an ophthalmically acceptable carrier in sufficient concentration so as to deliver an effective amount of the active compound or compounds to the optic nerve site of the eye. Preferably, the ophthalmic, therapeutic solutions contain one or more of the active compounds in a concentration range of approximately 0.0001% to approximately 5% (weight by volume) and more preferably approximately 0.0005% to approximately 0.1% (weight by volume). An ophthalmically acceptable carrier does not cause significant irritation to the eye and does not abrogate the pharmacological activity and properties of the charged sodium channel blockers. Ophthalmically acceptable carriers are generally sterile, essentially free of foreign particles, and generally have a pH in the range of 5-8. Preferably, the pH is as close to the pH of tear fluid (7.4) as possible. Ophthalmically acceptable carriers are. for example, sterile isotonic solutions such as isotonic sodium chloride or boric acid solutions. Such carriers are ty pically aqueous solutions contain sodium chloride or boric acid. Also useful are phosphate buffered saline (PBS) solutions. Various preservatives may be used in the ophthalmic preparation. Preferred preservatives include, but are not limited to, benzalkonium potassium, chlorobutanol, thimerosal. phenylmercuric acetate, and phenylmercuric nitrate. Likewise, various preferred vehicles may be used in such ophthalmic preparation. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose and hydroxyethyl cellulose. Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, etc., mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. Ophthalmically acceptable antioxidants can also be include. Antioxidants include but are not limited to sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxy anisole, and butylated hydroxytoluene. Formulations for Nasal and Inhalation Administration The pharmaceutical compositions of the invention can be formulated for nasal or intranasal administration. Formulations suitable for nasal administration, when the carrier is a solid, include a coarse powder having a particle size, for example, in the range of approximately 20 to 500 microns which is administered by rapid inhalation through the nasal passage. When the carrier is a liquid, for example, a nasal spray or as nasal drops, one or more of the formulations can be admixed in an aqueous or oily solution and inhaled or sprayed into the nasal passage. For administration by inhalation, the active ingredient can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, di chloro tetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of, for example, gelatin or blisters of, for example, laminated aluminum foil, for use in an inhaler or insufflator. Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier / diluent / excipient substance) such as mono-, di or ploy-saccharides (e.g. lactose or starch). Use of lactose is preferred. In one embodiment, each capsule or cartridge may contain between about 2 ug to about 100 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. In a preferred embodiment, each capsule or cartridge may contain between about 10 ug to about 50 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. In another embodiment, each capsule or cartridge may contain between about 20 ug to about 10 mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be delivered without excipients. Suitably, the packaging / medicament dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), single use inhaler (capsule or blister inhaler), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI). Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain an aqueous medium, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient(s); a propellant as solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Compositions formulated for nasal or inhalation administration may include one or more taste-masking agents such as flavoring agents, sweeteners, and other strategies, such as sucrose, dextrose, and lactose, carboxylic acids, menthol, amino acids or amino acid derivatives such as arginine, lysine, and monosodium glutamate, and / or synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plants, leaves, flowers, fruits, etc. and combinations thereof. These may include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry. cherry, plum, pineapple, apricot, etc. Additional sweeteners include sucrose, dextrose, aspartame, acesulfame-K, sucralose and saccharin, organic acids (by non-limiting example citric acid and aspartic acid). Such flavors may be present at from about 0.05 to about 4 percent by weight and may be present at lower or higher amounts as a factor of one or more of potency of the effect on flavor, solubility of the flavorant, effects of the flavorant on solubility or other physicochemical or pharmacokinetic properties of other formulation components, or other factors. Methods of Use The present application also provides therapeutic methods and uses comprising administering the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic agents or palliative agents. In some embodiments, provided is a method for the treatment of one or more inflammatory-related diseases or disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof. In some embodiments, provided is a method for the treatment of one or more inflammatory-related diseases or disorders in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent, which amounts are together effective in treating said one or more inflammatory -related diseases or disorders. In some embodiments, provided is also a method for the treatment of a disease or disorder mediated by calcineurin in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disease or disorder, in particular an inflammatory-related disease or disorder. In some embodiments, provided is also a method of inhibiting calcineurin in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit calcineurin. The treatment regimen for the compound of the invention that is effective to treat one or more inflammatory-related diseases or disorders patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti- inflammatory response in the subject. While an embodiment of any of the aspects of the present application may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test know n in the art such as the Student's t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat-testy and the Wilcon on-test. In some embodiments, this application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising systemically administering to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising parenterally administering to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, parenteral administration includes, but is not limited to, subcutaneous administration, intramuscular administration, intravenous administration, and intrathecal administration. In some embodiments, parenteral administration is subcutaneous administration. In some embodiments, parenteral administration is intramuscular administration. In some embodiments, parenteral administration is intravenous administration. In some embodiments, parenteral administration is intrathecal administration. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising administering via inhalation to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the application includes a method of treating a disease or disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of a compound disclosed herein. In some embodiments, the application includes a method of treating a condition or disorder associated with abnormal Calcineurin activity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in skin cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application includes a method of treating a disease or disorder characterized by elevated calcineurin activity in ocular cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the application also provides for a method for delaying in patient the onset of an inflammatory-related disease or disorder comprising the administration of a therapeutically effective amount of the compound of the invention to a patient in need thereof. In some embodiments, the application also provides a method of protecting a kidney by reducing immunosuppression-induced nephrotoxicity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the invention. Preferably, a kidney is a transplanted kidney. In some embodiments, the compound of the invention may be administered in combination with a standard of care agent. In some embodiments, the compound of the invention may be administered in combination with an additional therapeutic agent or treatment. In some embodiments, the compound of the invention exhibits reduced nephrotoxicity compared to the existing CNIs as described herein, such as tacrolimus. In some embodiments, the compound of the invention exhibits reduced nephrotoxicity compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease. In some embodiments, the compound of the invention exhibits improved bioavailability compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease. In some embodiments, the compound of the invention exhibits reduced variability of exposure compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease. In some embodiments, the compound of the invention exhibits reduced food effects compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease. In some embodiments, the compound of the invention exhibits reduced maximum-to-minimum concentration (Cmax / Cmin) ratio compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease. In some embodiments, the compound of the invention exhibits reduced patient nonadherence compared to the existing CNIs as described herein, such as tacrolimus, for the treatment of the same condition or disease. Indications The compounds, compositions, methods, and kits of the invention can be used to treat diseases or disorders, preferably inflammatory-related diseases or disorders. In some embodiments, the application includes a compound for use in the treatment and / or prevention of inflammatory-related diseases or disorders. In some embodiment, the application provides use of a compound for the manufacture of a medicament for treating inflammation-related diseases or disorders. The application also provides a method of treatment of systemic disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound of the invention. The compound of the invention can be administered to the subject in need through any route of administration as described herein. In some cases, it is systemically administered. In some cases, it is orally administered. In some cases, it is administered via subcutaneous administration. In some cases, it is administered via ophthalmic drug administration (e.g., eye drops). In some cases, it is administered via pulmonary drug delivery (e.g., inhaler). In some cases, it is administered through topical administration. In some embodiments, the inflammation-related disease or disorder includes but is not limited to periodontitis, keratoconjuncitivitis sicca, rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft versus host disease, systemic lupus erythematosus, cutaneous lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis. Behcet's disease, spondylitis, endometriosis, non-articular inflammatory conditions, such as itch. Intervertebral disk syndrome conditions, bursitis, tendonitis, tenosynovitis or fibromyalgia syndrome; and acute or chronic pain, including but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Holton's disease, varicose ulcers, neuralgias. Musculo-skeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, veltebral pain, post-surgety pain, herniated intervertebral disc—induced sci2Jica, cancer- related pain, vascular pain, visceral pain, childbirth, HIV-related pain, a metabolic disease, a chemotherapy / radiation related complication; diabetes type 1: diabetes type II; a liver disease; a gastrointestinal disorder; an ophthalmological disease; allergic conjunctivitis; diabetic retinopathy; Sjogren's syndrome; uveitis; a renal disease; HV-related cachexia; cerebral malaria; ankylosing spondylitis; leprosy; anemia; fibromyalgia, kidney failure, stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure such as heart failure, aoltic valve stenosis, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass: hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), dot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary’ occlusion, acute peripheral arterial occlusion, massive pulmonary embolism, axillary vein thrombosis, massive iliofemoral vein thrombosis, occluded arterial or venous cannulae, cardiomyopathy, venoocclusive disease of the liver, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, diminished lung compliance, leukopenia or thrombocytopenia, or atherosclerosis. In some embodiments, the application includes a method of preventing organ transplant rejection. In some embodiments, the organ transplant is kidney, liver, heart, lung, pancreas, or intestine. In some embodiments, the application includes a method of treating an infection. In some embodiments, an infection is a fungal infection. In some embodiments, the application includes a method of preventing organ transplant rejection and the organ is preferably a kidney. In some embodiments, the application includes a method of treating a disorder or condition associated with kidney transplant in a subject in need. The method comprises administering to the subject in need a therapeutically effective amount of the compound of the invention. Preferably, the method comprises systematically administering to the subject in need a therapeutically effective amount of the compound of the invention, e.g., via oral administration, intravenous administration, intramuscular administration, subcutaneous administration, inhalation administration, or rectal administration; preferably, oral or subcutaneous administration. In some embodiments, the application includes a method of treating or ameliorating lupus nephritis in a subject in need. In some embodiments, the application includes a method of treating a disorder or condition associated with lupus nephritis in a subject in need. In some embodiments, the application includes a method of treating or ameliorating ANCA-associated vasculitis in a subject in need. In some embodiments, the application includes a method of treating a disorder or condition associated with ANCA-associated vasculitis in a subject in need. The method comprises systematically administering to the subject in need a therapeutically effective amount of the compound of the invention, e.g., via oral administration, intravenous administration, intramuscular administration, subcutaneous administration, inhalation administration, or rectal administration; preferably, oral or subcutaneous administration. In some embodiments, the application includes the methods of treating inflammatory-related diseases or disorders, including skin or ocular disorders. In some embodiments, the application includes a compound for use in the treatment and / or prevention of inflammatory-related diseases or disorders. Thus, in one embodiment, the application provides use of a compound for the manufacture of a medicament for treating and / or inflammatory-related diseases or disorders. The application also provides a method of treatment of a skin disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the application. The application also provides a method of treatment of an ocular disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the application. In some embodiments, the inflammatory-related disease or disorder is a skin disease or disorder. In some embodiments, a skin disease or disorder is selected from the group consisting of psoriasis, dermatitis, eczema (also known as atopic dermatitis), hives, lichen planus, lichen scleroses, vitiligo, discoid lupus, cutaneous lupus erythematosus and pityriasis alba. In some embodiments, a skin disease or disorder is psoriasis. In some embodiments, a skin disease or disorder is dermatitis. In some embodiments, a skin disease or disorder is eczema. In some embodiments eczema is seborrheic eczema. In some embodiments, dermatitis is selected from the group consisting of contact dermatitis, atopic dermatitis, nummular dermatitis, seborrheic dermatitis, and stasis dermatitis. Preferably, the compound of the invention is administered topically. In some embodiments, an inflammatory -related disease or disorder is an ocular disease or disorder. In some embodiments an ocular disease or disorder is selected from the group consisting of dry’ eye syndrome (DES), Sjogren's syndrome, uveitis (such as refractory’ anterior uveitis), conjunctivitis (pink eye), keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), autoimmune disorders of the ocular surface, including cicatrizing conjunctivitis, blepharitis, and scleritis. In some embodiments an ocular disease or disorder is dry eye syndrome (DES). In some embodiments an ocular disease or disorder is Sjogren's syndrome. In some embodiments an ocular disease or disorder is uveitis, preferably refractory’ anterior uveitis. Preferably, the compound of the invention is administered via ophthalmic drug administration (e.g., eye drops). In some embodiments, the application includes a method of treating an infection. In some embodiments, an infection is a fungal infection. In some embodiments, a fungal infection is a nail fungal infection. In some embodiments, a fungal infection is a toenail fungal infection. In some embodiments, a fungal infection is a fingernail fungal infection. In some embodiments, the application includes the methods of treating inflammatory-related diseases or disorders, including pulmonary disorders. In some embodiments, the application includes a compound for use in the treatment and / or prevention of inflammatory-related diseases or disorders. Thus, in one embodiment, the application provides use of a compound for the manufacture of a medicament for treating and / or inflammatory - related diseases or disorders. The application also provides a method of treatment of a pulmonary disease or disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the application. In some embodiments, infl animator}'-related disease or disorder is a pulmonary' disease or disorder. In some embodiments, a pulmonary disease or disorder is selected from the group consisting of allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respirator}' tract inflammation. In some embodiments, the application includes a method of preventing organ transplant rejection. In some embodiments, the organ is lung. In some embodiments, the application includes a method of treating a disorder or condition associated with lung transplant in a subject in need. The method comprises administering to the subject a therapeutically effective amount of the compound of the invention. Conditions requiring lung transplant include but are not limited to chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension. In some cases, the subject is a recipient of transplanted lung. In some cases, the disorder or condition associated with lung transplant is a post-transplant complication. In some cases, the disorder or condition associated with lung transplant is a post-transplant complication including graft rejection wherein the recipient’s immune system treats the transplanted lung as foreign and mounts an immune response, i.e., graft-versus-host disease (GvHD), infections, bronchiolitis obliterans syndrome (BOS), and other postoperative complications. In some embodiments, the application includes a method of treating a pulmonary disease or disorder in a subject in need. In some embodiments, the subject is diagnosed with asthma, such as steroid-unresponsive asthma. In some embodiments, the pulmonary disease or disorder includes asthma (such as steroid-unresponsive asthma), chronic obstructive pulmonary disease (COPD), cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension, bronchiectasis, sarcoidosis, interstitial lung disease (ILD), pneumonia, tuberculosis. In some embodiments, the pulmonary disease or disorder is asthma, such as steroid-unresponsive asthma. Preferably, the compound of the invention is administered systematically such as oral or subcutaneous administration. Preferably, the compound of the invention is administered via pulmonary drug delivery such as using an inhaler. Definitions As used in this specification and the appended claims, the singular forms “a”, "an", and “the’’ include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods, and / or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. The term “comprising”, which is used interchangeably with “including”, “containing”, or “characterized by”, is inclusive or open-ended language and does not exclude additional, unrecited elements or method steps. The phrase “consisting of excludes any element, step, or ingredient not specified in the claim. The phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The application contemplates embodiments of the invention compositions and methods corresponding to the scope of each of these phrases. Thus, a composition or method comprising recited elements or steps contemplates particular embodiments in which the composition or method consists essentially of or consists of those elements or steps. By “inflammation” is meant any types of inflammation, such those caused by the immune system (immune-mediated inflammation) and any symptom of inflammation, including redness, heat, swelling, pain, and / or loss of function. The term “pain” is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g., somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain. Pain receptors for tissue injury are located mostly in the skin, musculoskeletal system, or internal organs. By “patient” it means any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods, compositions, and kits of the invention include but are not limited to non-human primates (e.g.. monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds). Compounds useful in the invention include, but are not limited to, those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein. The term '‘pharmaceutically acceptable salt” represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 4 carbon atoms or Ci-4 alkyl of C1-C4 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alky l group from 1 to 4 carbon atoms includes each of Ci, C2, C3, and C4 alkyls. Other numbers of atoms and other types of atoms may be indicated in a similar manner. “D” is deuterium. As used herein, the terms “alkyd” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms or 3 to 7 carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. By “C1-4 alky1” or “C1-C4 alky l” is meant a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms. Similarly, a “C1-6 alkyd” or “Ci-Ce” is a branched or unbranched hydrocarbon group having from 1 to 6 carbon atoms. A “C1-3 alkyl” or “C1-C3” is a branched or unbranched hydrocarbon group having from 1 to 3 carbon atoms. An alkyl, including, for example, a Ci-4 alkyl or Ci-6 alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. Exemplary substituents also include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Ci-4 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, secbutyl, tert-butyl, and cyclobutyl. Ci-6 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl, and cyclohexyl. An example of a substituted alkyl is a heteroalkyl. By “heteroalky 1” is meant a branched or unbranched alkyl, cycloalkyl, alkenyl, or alkynyl group having one or more heteroatoms in place of the carbon atoms independently selected from the group consisting of N, O, and S. By “C1-7 heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, 0, S, and P. Heteroalkyls can include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalky l group may be substituted or unsubstituted. Exemplary substituents include alkyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide (F, Cl, Br or I), hydroxyl, fluoroalkyl, perfluoralkyl, oxo, amino, alkylamino, disubstituted amino, quaternary amino, amido, ester, alkylcarboxy, alkoxycarbonyl, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinato, acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido). amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, aryl, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of C1-7 heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl. An alkenyl is a branched or unbranched hydrocarbon group containing one or more double bonds. For example, by “C2-6 alkenyl” or “C2-C6 alkenyl” is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms. An alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The alkenyl group may be substituted or unsubstituted. Exemplary substituents include those described above for alkyl, and specifically include alkoxy, aryloxy. sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, and carboxyl groups. C2-6 alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, and 2-methyl-2-propenyl. An alkynyl is a branched or unbranched hydrocarbon group containing one or more triple bonds. For example, by “C2-6 alkynyl” or “C2-C6 alky nyl” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms. An alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The alkynyl group may be substituted or unsubstituted. Exemplary substituents those described above for alkyl, and specifically include alkoxy, aryloxy, sulfhydryl, alkydthio, arydthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary' amino, alkylcarboxy, and carboxyl groups. C2-6 alkynyls include, without limitation, ethynyl, 1-propynyl. 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. By “heterocyclyl,” “heterocyclic,” or “heterocycloalkyd” is meant a stable monocyclic or polycyclic (including a bicyclic or a tricyclic) heterocyclic ring which is saturated, partially unsaturated or unsaturated (including heteroaryd or aromatic), and which consists of 2 or more carbon atoms and 1, 2, 3, 4 or more heteroatoms independently selected from N, O, and S and including any bicyclic or polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, heteroaryd, cycloalkyd or heterocycloalkyl. A “3-to 6- membered heterocycloalkyl” is mean to refer to a heterocyclic ring having 3 to 6 ring atoms wherein at least one ring atom is a heteroatom selected from N, 0. and S. Similarly, a “3- to 10- membered heterocycloalkyl” is mean to refer to a heterocyclic ring having 3 to 10 ring atoms wherein at least one ring atom is a heteroatom selected from N, O, and S. In certain aspects, the heterocyclyl is a 3- to 15-membered ring system, a 3- to 12- membered ring system, or a 3- to 9-membered ring system. By “C2-6 heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (including heteroaryl or aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, heteroaryl, cycloalkyd or heterocycloalky1. The heterocyclyl or heteroaryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, ary loxy. sulfhydry 1, alkylthio, arylthio, halide, hydroxy, fluoroalky l, perfluoralkyl, amino, alkylamino, disubstituted amino, quaternary amino, alkylcarboxy, oxo, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle can be quatemized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation. IH-indazole. 2-pyrrohdonyl. 2H,6H-l,5,2-dithiazinyL 2H-pyrrolyL 3H-indolyl, 4-piperidonyl. 4aH-carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazoly 1. b-carbolinyl. chromanyl. chromenyl, cinnolinyl. decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furany l, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl. pyrazolyl, pyridazinyl. pyridooxazole. pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl. quinolinyl, 4H-quinolizinyl, quinoxalinyl. quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1.2.5-triazolyl, 1.3.4-triazolyl, xanthenyl, p-lactam, y-lactam and 5-lactam. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl. and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl. Preferred substituents include phenyl, methyl, ethyl, propyl, butyl, chloro, bromo, fluoro, iodo and oxo. By “aryl” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated n electrons (e.g., phenyl). A “Ce-Cnaryl” or “Cs-Cio aryl” is an aryl group that has from 6 to 12 carbon atoms or 6 to 10 carbon atoms, respectively. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. A bicyclic or tricyclic ring system can be fused (e g., naphthyl) or not (e.g.. biphenyl). The aryl group may be substituted or unsubstituted. Exemplary substituents include substituted or unsubstituted alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, monosubstituted amino, disubstituted amino, and quaternary' amino groups. A preferred ary l group is phenyl. By “heteroaryl” it is meant an aromatic ring group having a ring system comprised of hetero atoms (such as N, O, S) and carbon atoms with conjugated n electrons (e.g., pyridine, pyrimidine, triazine). A “5- to 6- membered heteroaryl” refers to a heteroaryl having 5 to 6 ring atoms with conjugated it electrons wherein at least one ring atom is a heteroatom selected from N, O, and S. Similarly, a “5- to 12- membered heteroaryl” refers to a heteroaryl having 5 to 12 ring atoms with conjugated it electrons wherein at least one ring atom is a heteroatom selected from N, 0, and S. The heteroaryl groups can include monocyclic, bicyclic, or tricyclic rings, with each ring typically having five or six members. Bicyclic or tricyclic ring systems within heteroaryls can be fused (e.g., quinoxaline) or not. Heteroaryl groups may be substituted or unsubstituted, with possible substituents including various functional groups such as substituted or unsubstituted alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, alkylcarboxy, amino, alkylamino, monosubstituted amino, disubstituted amino, and quaternary amino groups. An example of a preferred heteroaryl group is a phenyl group with heteroatoms replacing one or more carbon atoms in the ring. By ’ aralkyl" is meant a substituted or unsubstituted alkyl that is substituted by a substituted or unsubstituted aryl (including, for example, (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl). By “C7-14aralkyl'’ is meant an alky l substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms. By “halide” or “halogen” is meant bromine, chlorine, iodine, or fluorine. By “fluoroalkyl” is meant an alkyl group that is substituted with a fluorine atom. By “alkylcarboxy” is meant a chemical moiety7 with the formula —(R)—COOH, wherein R is selected from C1-7 alkyl, C2-7 alkenyl, C2-7alkynyl, C2-6 heterocyclyl, Ce-i2aryl, C7-14 aralkyl, C3-10 heterocycloalkyl, or C1-7 heteroalkyl. By “alkoxy” is meant a chemical substituent of the formula —OR, wherein Risa substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl or R can be selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-6 heterocyclyl, C6-i2aryl, C 7-14 aralkyl. C3-10 heterocycloalkyl, or C1-7 heteroalkyl. By “aryloxy” is meant a chemical substituent of the formula —OR. wherein R is a Cs-12 aryl group. By “alkylthio” is meant a chemical substituent of the formula —SR, wherein R is selected from C1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C2-6 heterocyclyl, Ce-naryl, C7-14 aralkyl, C3-10 heterocycloalkyl, or C1-7 heteroalkyl. By “arylthio” is meant a chemical substituent of the formula —SR, wherein R is a Ce-12 aryl group. By “charged moiety" is meant a moiety which gains a proton at physiological pH thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium) or a moiety that includes a net formal positive charge without protonation (e.g., quaternary ammonium). The charged moiety may be either permanently charged or transiently charged. By “therapeutically effective amount” or “effective amount” means an amount sufficient to produce a desired result, for example, the reduction or elimination of any symptoms in a patient (eg., a human) suffering from an inflammatory-related disease or disorder. By “patient nonadherence’' as used herein refers to the failure or reluctance of patients to follow prescribed medical advice or treatment plans. In the context of organ transplantation and immunosuppressive therapy, nonadherence can manifest as patients not taking medications as prescribed, missing doses, altering doses without medical guidance, or discontinuing medications altogether. Nonadherence is a significant concern in transplantation because maintaining the proper balance of immunosuppressive medications is crucial to prevent organ rejection. The term “toxicity” refers to a condition that results in damage to the organism. By ■’nephrotoxicity" means a condition that results in damage to kidney. “Immunosuppression-induced nephrotoxicity” refers to a condition resulting in damage to kidney that is induced by administration of immunosuppressive regimens, such as administration of CNIs including tacrolimus. “Reduced immunosuppression-induced nephrotoxicity” means the condition has been ameliorated or eliminated because of the replacement of an existing CNI by a compound of this invention. By “food effect” as used herein means refer to the impact of food consumption on the pharmacokinetics of a drug, influencing its absorption, distribution, metabolism, and excretion. The presence of food in the gastrointestinal tract can affect the way a drug is absorbed, altering the rate and extent of its entry into the bloodstream. In certain embodiments, the compound of the invention reduces or eliminates the food effect. As used herein, “reducing the food effect” refers to narrowing the difference in bioavailability for a drug administered with or close to consumption of food in comparison to the drug administered without consumption of food for a certain period of time. In certain aspects, the food effect is eliminated. Thus, upon oral administration of a compound of the invention to a subject in need thereof, there is not a significant food effect. In other words, the difference between a pharmacokinetic parameter measured after oral administration to a mammal with and without food, respectively, is less than 40%, e.g., less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10 or less than 5%. Preferably the composition or the pharmaceutical composition of the invention has at least 15% reduced food effect, preferably 20%, preferably 25%, preferably 30%, preferably 40%, reduced food effect. By “bioavailability” it indicates the extent to which a drug or another substance, especially a CNI, is utilized systematically or by a target tissue after administration. Changes in bioavailability can impact the therapeutic efficacy and safety of a drug. The compounds of the present invention, including salts of the compounds, can exist in unsolvated forms as well as solvated forms, including hydrated forms and unhydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Nonlimiting examples of hydrates include monohydrates, dihydrates, hemihydrates, etc. In certain aspects, the compound is a hemihydrate. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. The compounds of the present invention, including salts of the compounds, can exist in unsolvated forms as well as solvated forms, including hydrated forms and unhydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Nonlimiting examples of hydrates include monohydrates, dihydrates, hemihydrates, etc. In certain aspects, the compound is a hemihydrate. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. The compounds of the invention may exist in multiple cry stalline or amorphous forms. In general, all physical forms are equivalent for uses contemplated by the present invention and are intended to be within the scope of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. Examples Synthesis of the compounds As an example, the synthesis of Compound 9 was presented below in Steps 1-6. In the preparation of intermediates, each of the four ring moieties was synthesized and labeled from left to right as A, B, C, and D as shown below: Step 1. Synthesis of the A ring moiety: EtONa, EtOHO-25 °C Mel, K2CO3 60 °C KOH, DMSO, H2O 100 °C BnBr, NaHCO3 50 °C HCI, Dioxane 25 °C Step 2. Synthesis of the B ring moiety (the core quinazoline moiety): Step 3. Synthesis of the AB moiety Step 4. Synthesis of the D ring moiety 1) NaH, 0-25 °C 2) n-BuLi, 78°C to 60 °C Ococ Mel, K2CO3 60 °C Step 5. Synthesis of the CD ring moiety Step 6. Synthesis of Compound 9. Reaction conditions including reagents and temperatures for each step were shown in the synthetic schemes above. Coupling reactions were carried out using N,N'-diisopropylcarbodiimide (DIC) at room temperature. Deprotection for benzyl was achieved using 10% Pd / C and hydrogen gas (15 psi) at 25 °C. Deprotection for methoxymethyl (MOM) group was achieved using HC1 at 25 °C. Other compounds as described herein were synthesized following synthetic schemes analogous to the synthesis of Compound 9. Additional examples for synthesizing the intermediate moieties were provided below. Synthesis of the intermediate AB moiety of Compound 1: MOMCI, NaHCO3 70°C Synthesis of the intermediate AB moiety of Compound 2: Synthesis of the intermediate AB moiety of Compound 3: Synthesis of the intermediate AB moiety of Compound 4: Synthesis of the intermediate CD moiety of Compound 5: 1. Oxalyl chloride, DMF Synthesis of the intermediate C moiety of Compound 8: BnBr, K2CO3        0 i I _      60 °C          JL JL ► Et0 p if ■^^OH 1          MOMBr, DIEA        £ 25 °C    MOMO^ y^OBn             MOMOX Br NBS        if 1         KOH, DMSO, H2O /   25 °C EtO^YlI^       100 °C » HO^ty^OBn OBn                     I Br I           wetPd / C, H2(15psi)         |?    | 25 °C MOMO^YY I^^OBn              MOMO^y^On Br                                             Br Synthesis of the intermediate CD moiety of Compound 8: HCI, r.t. Characterization of exemplary compounds using LCMS and NMR were provided in Table 2. Table 2. Characterization of exemplary compounds Compound No. LCMS m / z NMR 1 803.2 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 10.85 (br s, 1H), 8.54 (s, 1H), 7.39 (s, 1H), 6.55 (br m, 1H). 6.12 (s. 1H), 5.67 (s. 1H), 3.85 (s, 3H), 3.01 (s, 3H), 2.66 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.16 (br s, 3H), 2.08 (s, 3H), 1.98 (s, 3H), 1.04 (t, J = 7.6 Hz, 3H) 2 789.3 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 8.53 (s, 1H), 7.39 (s, 1H), 6.55 (br s, 1H). 6.12 (s, 1H). 5.67 (s. 1H), 3.85 (s. 3H), 3.00 (s, 3H), 2.64 (s, 3H), 2.46 (s, 3H), 2.27 (s, 6H), 2.15 (br s, 3H), 2.07 (s, 3H), 2.02 (s, 6H) 3 809.3 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 10.88 (br s, 1H), 8.59 (s, 1H), 7.43 (s, 1H), 6.57 (br s, 1H), 6.15 (s, 1H), 5.70 (s, 1H), 3.88 (s, 3H). 3.04 (s, 3H), 2.67 (s, 3H), 2.49 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.19 (br s, 3H), 2.15 (s, 3H), 2.10 (s, 3H) 4 775.2 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 10.88 (br s, 1H), 8.59 (s, 1H), 7.40 (s, 1H), 6.89 (s, 1H), 6.62 (br s, 1H), 6.15 (s, 1H), 5.70 (s, 1H), 3.88 (s, 3H), 3.00 (s, 3H), 2.66 (s, 3H), 2.49 (s, 3H), 2.35 (s, 6H), 2.19 (br s, 3H), 2.10 (s, 3H), 2.09 (s, 3H) 5 737.5 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 8.55 (s, 1H), 7.45 (d, 1H), 6.46 (br, 1H), 6.14 (m, 1H). 5.68 (d. 1H). 3.85 (s, 3H). 3.03 (s. 3H), 2.64 (m, 5H), 2.53 (br s, 3H), 2.45 (br s, 3H), 2.32(s, 3H), 2.26 (s, 3H), 2.10 (d, 3H), 2.07 (s, 6H), 1.98 (s, 3H), 1.05 (t, 3H) 6 723.5 [M+H]+ 'H NMR (500 MHz, THF-ds) 5 ppm 8.54 (s, 1H), 7.44 (d, 1H), 6.43 (br, 1H), 6.14 (m, 1H). 5.68 (d. 1H). 3.85 (s, 3H). 3.02 (s. 3H), 2.63 (s, 3H), 2.44 (s, 6H), 2.27(s, 6H), 2.10 (d, 3H), 2.07 (s, 6H), 2.03 (s, 6H) 7 723.2 [M-H]- 'H NMR (400 MHz, THF-ds) 5 ppm 8.58 (s, 1H), 7.42 (s, 1H), 6.72 (s, 1H), 6.45 (s, 1H), 6.13 (1. J = 1.5 Hz. 1H), 5.68 (d. J = 1.4 Hz, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 3.00 (s, 3H), 2.62 (s, 3H), 2.44 (s, 6H), 2.28 (s, 3H), 2.10 (d, J = 1.5 Hz, 3H), 2.06 (s, 6H), 2.02 (s, 3H) 8 771.3 [M+H]+ 'H NMR (400 MHz, DMSO-de) 5 ppm 8.68 (s. 1H), 7.50 (s, 1H), 5.76 (m, 2H). 2.97 (s, 3H). 2.83-2.73 (m, 2H). 2.58 (s. 3H), 2.56-2.54 (m. 2H), 2.33 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.00 (s, 3H), 1.92 (s, 6H), 1.81 (br s, 3H), 1.47 (s, 3H), 0.98 (t, J = 7.6 Hz, 3H) 9 792.2 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 8.58 (s, 1H), 7.38 (s, 1H), 6.72 (s, 1H), 6.49 (s, 1H), 6.12 (s. 1H), 5.67 (s. 1H), 3.85 (s, 3H), 3.74 (s, 3H). 2.98 (s, 3H), 2.64 (s, 3H), 2.47 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 2.03 (s, 3H) 10 721.4 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 8.58 (s, 1H), 7.47 (s, 1H), 6.23 (s, 2H). 3.04 (s, 3H). 2.64 (s. 3H), 2.50 - 2.40 (m. 2H), 2.44 (s, 6H), 2.33 (s, 3H), 2.27 (s, 3H), 2.15 (s, 6H), 2.07 (s, 6H), 1.99 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H) 11 691.5 [M+H]1 'H NMR (400 MHz, THF-ds) 5 ppm 8.56 (s, 1H), 7.46 (s, 1H), 5.77 (m, 2H). 3.05 (s, 3H). 2.88-2.75 (m, 2H). 2.65 (s. 3H), 2.45 (s. 6H), 2.29 (s, 6H), 2.11 (s, 6H), 2.06 (s, 6H), 1.90 (s, 6H), 1.52 (s, 3H) 12 803.4 [M+H]1 'H NMR (500 MHz, THF-ds) 5 ppm 10.86 (br, 1H), 8.56 (s, 1H), 7.45 (s, 1H), 6.60 and 6.51 (br. 1H), 6.13 (I. 1H), 5.67 (s, 1H), 3.85 (s. 3H). 3.05 (s, 3H). 2.67 (s. 3H), 2.64 (2H), 2.61 (s, 3H), 2.46 (s. 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.16 (br, 6H), 1.98 (s, 3H), 1.04 (t, J = 8Hz, 3H) 13 753.4 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 8.55 (s, 1H), 7.37 (d, 1H), 6.48 (br, 1H), 6.14 (m, 1H). 5.68 (d. 1H). 3.86 (s, 3H). 3.84 (s. 3H), 3.03 (s, 3H), 2.67 (s, 3H), 2.63 (q, J = 8Hz, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), 2.11 (d, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.05(1, J = 8Hz. 3H) 14 758.4 [M+H]+ 'H NMR (400 MHz, THF-ds) 5 ppm 10.85 (br. 1H), 8.56 (s. 1H), 7.45 (s, 1H), 6.53 (br, 1H), 6.14 (t, 1H), 5.67 (s, 1H), 3.85 (s, 3H), 3.03 (s, 3H), 2.67 (s, 3H), 2.64 (q, 2H), 2.41 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.13 (br, 6H), 1.98 (s, 3H), 1.29 (s, 3H). 1.06 (t, J = 8Hz, 3H) Synthesis of Example 15: SelectFlour (1.2 Equiv.) methyl 3-fluoro-4,6-dihydroxy-2,5-dimethylbenzoate To a cooled (0 °C) solution of methyl 2,4-dihydroxy-3,6-dimethylbenzoate (6000 mg, 1 Eq, 30.58 mmol) in MeCN (100 mL) was added Selectfluor (13.00 g. 1.2 Eq. 36.70 mmol), the mixture allowed to stir for 16 h at room temperature. Them, reaction mixture was filtered through a plug of Celite(R). The filtrate was evaporated, the residue was treated with aq. sat. NH4C1 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine and dried over MgSO4. Purification by FC on SiO20 to 30 % EtOAc in CyH afforded the pure product as a colourless solid (1.72 g, 8.03 mmol, 26.3 %). 'H NMR (400 MHz, CDCh) 5 11.73 (s, 1H), 5.70 (d, J= 6.5 Hz, 1H), 3.93 (s, 3H), 2.41 (dd, J = 2.8, 0.7 Hz, 3H), 2.14 (d, J = 0.7 Hz, 3H). BnBr (1.05 Equiv.) K2CO3 (1.2 Equiv) Methyl 4-(benzyloxy)-3-fluoro-6-hydroxy-2,5-dimethylbenzoate To a solution of methyl 3-fluoro-4,6-dihydroxy-2,5-dimethylbenzoate (1.72 g, 1 Eq, 8.03 mmol) in MeCN (50 mL) was added K2CO3 (1.33 g, 1.2 Eq, 9.64 mmol) and benzyl bromide (1.44 g, 1.00 mL, 1.05 Eq, 8.43 mmol), the mixture was stirred at 50 °C for 2 h. The reaction was quenched by the addition of 10 % aq. citric acid and extracted with ether 3 times, then dried over MgSO4 and evaporated. Purified by FC to afford the product as a colourless solid (2.16 g, 7.10 mmol, 88.4%) 'HNMR (400 MHz, CDCh) 5 11.49 (s, 1H), 7.47 - 7.34 (m, 7H), 5.12 - 5.10 (m, 2H), 3.95 (s, 3H). 2.44 (dd, J= 2.9, 0.7 Hz, 3H), 2.10 (d, J = 0.7 Hz, 3H). Methyl 4-(benzyloxy)-3-fluoro-2,5-dimethyl-6-(((trifluoromethyl)sulfonyl)oxy)benzoate To a solution of methyl 4-(benzyloxy)-3-fluoro-64iydroxy-2,5-dimethylbenzoate (2.16 g, 1 Eq. 7.10 mmol) cooled to 0 °C in DCM (60 mL) was added pyridine (1.68 g. 1.72 mL. 3 Eq. 21.3 mmol) followed by Trifluoromethanesulfonic Anhydride (3.00 g, 1.79 mL, 1.5 Eq, 10.6 mmol). The resulting mixture was stirred for 1 h at that temperature, the reaction was quenched by the addition of 10 % aq. citric acid, and the aq. phase was extracted with DCM. The combined organic phases were washed with NaHCOs and brine. Purification by FC SiO2 0 to 30 % EtOAc in CyH afforded the pure product as a colourless solid (2.80 g, 6.42 mmol, 90.4 %). ’H NMR (400 MHz, CDCh) 5 7.44 - 7.34 (m, 1H), 5.15 (d, .7=1.3 Hz, OH), 3.92 (s, 1H), 2.37 - 2.29 (m, 1H), 2.18 (s, 1H). 1) Pd(OAc)2 (20 mol %) BINAP   (40 mol %)          Q 9 I                 Cs2CO3  (3 Equiv.)              JI    I Ph2C=NH (2 Equiv.) Me0>jfjr TfCTy^OBn 2) HCI                H2NXy^OBn Methyl 2-amino-4-(benzyIoxy)-5-fluoro-3,6-dimethylbenzoate A Schlenk flask was charged with diphenylmethanimine (384 mg, 355 pL, 2 Eq, 2.12 mmol), methyl 4-(benzyloxy)-3-fluoro-2,5-dimethyl-6-(((trifluoromethyl)sulfonyl)oxy)benzoate (462 mg, 1 Eq, 1.06 mmol), Palladium diacetate (47.5 mg, 0.2 Eq, 212 pmol), Cs2CO3 (1.03 g, 3 Eq, 3.18 mmol) and BINAP (264 mg, 0.4 Eq, 423 pmol). Toluene (12 mL) was added, and the solution was degassed by bubbling with nitrogen for 10 min. The mixture was heated to 80 °C until complete consumption of starting material. The reaction was quenched by the addition of aq. sat NEE and extracted with ether (3 x 20 mL). The combined organic layers were washed with brine and dried over MgSO4. The Solvent was evaporated, the residue was dissolved in THF (15 mL) and treated with 4 M aq. HCL at 50 °C until LC / MS showed full conversion. The reaction was quenched with NaHCOs and extracted with EtOAc (3x 10mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed and the residue purified by FC on SiO2 0 to 30 % EtOAc in CyH to afford the desired as a slight yellow solid (221 mg, 729 pmol, 68.8 %). 'll NMR (400 MHz, CDCh) 5 7.52 - 7.32 (m, 5H), 5.06 (s, 3H), 3.90 (s, 3H), 2.36 (d, J= 2.9 Hz. 3H), 1.99 (s, 3H). 7-(benzyloxy)-6-fluoro-5,8-dimethylquinazoIin-4(3H)-one Methyl 2-amino-4-(benzyloxy)-5-fluoro-3,6-dimethylbenzoate (216 mg, 1 Eq, 712 pmol) was heated with Formamidine Acetate (148 mg, 2 Eq, 1.42 mmol) in EtOH at 90 °C for 12. Then additional Formamidine Acetate (148 mg, 2 Eq, 1.42 mmol) and dioxan was added and heated to 90 °C for 16 h. The solvent was removed to afford the desired as a colourless solid (160 mg, 536 pmol, 75.3 %). 'HNMR(400 MHz, DMSO) 5 8.01 (s, 1H). 7.51 - 7.33 (m, 6H), 5.12 (s. 2H), 2.68 (d, J= 2.9 Hz. 3H), 2.33 (s, 3H). 7-(benzyloxy)-4-chloro-6-fluoro-5,8-dimethylquinazoline To 7-(benzyloxy)-6-fluoro-5,8-dimethylquinazolin-4-ol (158 mg, 1 Eq. 530 pmol) was added POCh (4.87 g, 2.96 mL, 60 Eq, 31.8 mmol) and the mixture was heated to 120 °C for 2h. The volatiles were removed under reduced pressure, the residue was taken up in DCM, washed with sat. aq. NaHCOs and dried over MgSO4. After evaporation of the solvent, the residue was used without further purification. 'H NMR (400 MHz, CDCh) 5 8.91 (s. 1H), 7.51 - 7.34 (m, 5H), 5.22 - 5.19 (m, 2H), 2.89 (dd, J = 3.1, 0.7 Hz, 3H), 2.57 (d, J = 0.7 Hz, 3H). Methoxymethyl 4-((7-(benzyloxy)-6-fluoro-5,8-dimethylquinazolin-4-yl)oxy)-2,3,5,6-tetramethylbenzoate To 7-(benzyloxy)-4-chloro-6-fluoro-5,8-dimethylquinazoline (151 mg, 1 Eq, 477 pmol) and methoxymethyl 4-hydroxy-2,3,5,6-tetramethylbenzoate (114 mg, 1 Eq, 477 pmol) in DMF (5 mL) was added CS2CO3 (171 mg, 1.1 Eq, 524 pmol) and stirred for 16 h at 60 °C. The reaction was quench by the addition of NH4CI and extracted with EtOAc (3x 15 mL). The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed and the residue purified by FC on SiC>4 0 to 30 % EtOAc in CyH to afford the desired product as a colourless solid (124 mg. 240 pmol, 50.3 %). 'H NMR (400 MHz. CDCh) 5 8.65 (s. 1H). 7.60 - 7.32 (m. 5H), 5.50 (s. 2H), 5.21 (s, 3H), 3.58 (s, 3H), 2.89 (d, J= 2.7 Hz, 3H), 2.61 (s, 3H), 2.29 (s, 7H), 2.05 (s, 7H). Pd / C (10 mol %), H2 Methoxymethyl 4-((6-fluoro-7-hydroxy-5,8-dimethylquinazolin-4-yl)oxy)-2,3,5,6-tetramethylbenzoate Methoxymethyl 4-((7-(benzyloxy)-6-fluoro-5,8-dimethylquinazolin-4-yl)oxy)-2,3,5,6-tetramethylbenzoate (150 mg, 1 Eq, 289 pmol) was dissolved int THF (5 mL), and Pd / C (30.8 mg, 10% Wt. 0.1 Eq. 28.9 pmol) was added. The mixture was stirred under an atmosphere of hydrogen for 2h. Then, the mixture was filtered through a plug of Celite (R), the solvent was removed under reduced pressure. The residue was purified by FC on SiO2 0 to 40 % EtOAc in CyH to afford the desired product as a colourless solid (82 mg, 0.19 mmol, 66 %) 'll NMR (400 MHz, DMSO) 6 8.50 (s, 1H), 5.48 (s, 2H), 3.50 (s, 3H), 2.88 - 2.75 (m, 3H), 2.54 - 2.47 (m. 3H), 2.19 (s, 6H), 1.96 (s, 6H). (R)-4-((7-((3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene- l-carbonyl)oxy)-5,6-dimethylbenzoyl)oxy)-6-fluoro-5,8-dimethylquinazolin-4-yl)oxy)-2,3,5,6-tetramethylbenzoic acid (Example 15) To a suspension of (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoic acid (25 mg, 1.2 Eq, 56 pmol) and methoxymethyl 4-((6-fluoro-7-hydroxy-5,8-dimethylquinazolin-4-yl)oxy)-2,3,5,6-tetramethylbenzoate (20 mg. 1 Eq. 47 pmol) in DCM (1 mL) was added a solution of EDC (11 mg, 1.2 Eq, 56 pmol) in DCM (0.5 mL) over 1 h via syringe pump. The reaction mixture was quenched by the addition of sat. aq. NH4CI. The aqueous phase was extracted with EtOAc (3x 10 mL). The combined organic phases were washed with 10 % citric acid and brine. The solvent was removed under reduced pressure. The residue was treated with HC1 (4 M in Dioxane, 1 mL) for 2 h. Then the solvent was removed and the reside purified by prep HPLC (H2O / MeCN) to afford the desired product as a colourless solid (4.90 mg, 11 %). LC-MS: m / z = 804.7 [M-H] 'H NMR (400 MHz, CD2CI2) 5 8.58 (s, 1H), 6.25 - 6.20 (m, 1H), 5.70 (s, 1H), 3.87 (s, 3H), 2.90 (d, J= 2.6 Hz, 3H), 2.65 (s, 3H), 2.56 (s, 3H), 2.27 (s, 6H), 2.18 (s, 3H). 2.06 (s, 3H), 2.01 (s. 6H). Other examples can be prepared according to the description of the procedure used for Example 15 by exchanging the respective reagents and precursors. Synthesis of Example 16 and Example 17: Step-1: Synthesis of 7-(benzyloxy)-4-chloro-2,5,8-trimethylquinazoline. 7-(benzyloxy)-2,5,8-trimethylquinazolin-4-ol (200 mg, 1 Eq, 679 pmol) was suspended in POC13 (6.25 g, 3.80 mL, 60 Eq, 40.8 mmol) in a sealed vial and heated to 120 °C for 4h. POC13 was then removed under reduced pressure, the crude was dissolved in DCM (10 mL) and washed twice with saturated aqueous sodium bicarbonate solution (2x10 mL). The combined aqueous phase was extracted twice with DCM (2x10 mL), The combined organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude residue was clean enough to be used directly in the next step. 1H NMR (400 MHz. CDC13) 6 7.48 - 7.31 (m, 5H), 7.19 (s, 1H). 5.29 (s, 2H). 2.98 (s. 3H), 2.87 (s, 3H), 2.65 (s, 3H). Step-2: Synthesis of methoxymethyl 4-((7-(benzyloxy)-2,5,8-trimethylquinazolin-4-yl)oxy)-3 -ethyl-2,5,6-trimethylbenzoate. 7-(benzyloxy)-4-chloro-2,5,8-trimethylquinazoline (205 mg, 1 Eq, 655 pmol) and methoxymethyl 3-ethyl-4-hydroxy-2,5,6-trimethylbenzoate (182 mg, 1.1 Eq, 721 pmol) were mixed in a sealed vial, and dissolved in DMF (5 mL). cesium carbonate (256 mg, 1.2 Eq, 786 pmol) and the resulting suspension was stirred at 60 °C for 4h. The reaction mixture was The reaction was quenched by saturated aqueous NH4C1 (20 mL), and the aqueous layer was extracted with EtOAc (3x15 mL). The combined organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude residue was purified by chromatography on silica gel to yield methoxymethyl 4-((7-(benzyloxy)-2,5,8-trimethylquinazolin-4-yl)oxy)-3-ethyl-2,5,6-trimethylbenzoate (210 mg, 61% over 2 steps) as a white solid. 1H NMR (400 MHz, CDC13) 5 7.53 - 7.35 (m, 5H), 7.10 (s, 1H), 5.51 (s, 2H), 5.28 (s, 2H), 3.60 (s, 3H), 2.91 (s, 3H), 2.75 - 2.42 (m, 8H), 2.32 (s, 3H), 2.26 (s, 3H), 1.94 (s, 3H), 1.02 (t, J = 7.5 Hz, 3H). Step-3: Synthesis of methoxymethyl 3-ethyl-4-((7-hydroxy-2,5.8-trimethylquinazolin-4-yl)oxy)-2,5,6-trimethylbenzoate. methoxymethyl 4-((7-(benzyloxy)-2,5,8-trimethylquinazolin-4-yl)oxy)-3-ethyl-2,5,6-trimethylbenzoate (210 mg, 1 Eq, 397 pmol) were dissolved in THF (20 mL), and Pd / C (10% w / w, 20mg) was added under nitrogen inert atmosphere. The mixture was placed under hydrogen atmosphere (1 atm, balloon) and the resulting suspension was stirred for 14h at RT. The suspension was then filtered over Celite and the filtrate was evaporated under reduce atmosphere to yield a crude residue which was purified by chromatography on silica gel to yield methoxymethyl 3-ethyl-4-((7-hydroxy-2,5,8-trimethylquinazolin-4-yl)oxy)-2,5,6-trimethylbenzoate. (120 mg, 69%) as a white solid. 1H NMR (400 MHz, CDC13) 5 6.92 (s, 1H), 5.49 (s, 2H), 3.58 (s, 3H), 2.85 (s, 3H), 2.63 -2.54 (m, 4H), 2.52 (s, 3H), 2.47 - 2.37 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.02 (t, J = 7.5 Hz, 3H). Step-4: Synthesis of 4-(2-ethyl-4-((methoxymethoxy)carbonyl)-3,5,6-trimethylphenoxy)-2,5,8-trimethylquinazolin-7-yl (R)-3-bromo-2-hydroxy-4-(( 1 -hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoate. To a solution of methoxymethyl 3-ethyl-4-((7-hydroxy-2,5,8-trimethylquinazolin-4-yl)oxy)- 2,5,6-trimethylbenzoate (15 mg, 1 Eq, 34 pmol) and and (R)-3-bromo-2-hydroxy-4-((l- hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l -carbonyl)oxy )-5,6- dimethylbenzoic acid (18 mg, 1.2 Eq, 41 pmol) in DCM (0.6 mL) was added EDCI (8.5 mg, 73 pmol) dissolved in DCM (0.6 mL) over 1 h and stirred at room temperature for 4 h. SiO2 was added and the solvent was evaporated, and the residue purified by column chromatography to provide the desired product 4-(2-ethyl-4-((methoxymethoxy)carbonyl)-3,5,6-trimethylphenoxy)-2,5,8-trimethylquinazolin-7-yl (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoate (10 mg, 12 pmol, 34 %) as a white powder. 1H NMR (400 MHz, CDC13) 5 7.16 (s, 1H), 6.29 (q, J = 1.5 Hz, 1H), 5.73 (d, J = 1.5 Hz, 1H), 5.52 (s, 2H), 3.86 (s, 3H), 3.60 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.64 - 2.55 (m, 7H), 2.45 - 2.36 (m. 1H), 2.33 (s, 3H), 2.27 (s, 3H), 2.25 - 2.12 (m, 3H), 2.05 (s, 3H), 1.95 (s, 3H), 1.02 (t, J = 7.5 Hz, 3H). Step-5: Synthesis of (R)-4-((7-((3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoyl)oxy)-2,5,8-trimethylquinazolin-4-yl)oxy)-3-ethyl-2,5,6-trimethylbenzoic acid = Example 16. 4-(2-ethyl-4-((methoxymethoxy)carbonyl)-3,5,6-trimethylphenoxy)-2,5,8-trimethylquinazolin-7-yl (R)-3-bromo-2-hydroxy-4-(( 1 -hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoate (10 mg, 1 Eq, 12 pmol) was dissolved in DCM (0.7 undefmedHCl (8.5 mg, 77 pL, 3 molar, 20 Eq, 0.23 mmol)) (3M in CPME) was added, and the mixture was stirred 16h at RT. The reaction mixture was then evaporated under reduced pressure, the residue was then washed with Et20 twice (trituration). After lyophilization, (R)-4-((7-((3-bromo-2-hydroxy-4-((l -hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoyl)oxy)-2,5,8- trimethylquinazolin-4-yl)oxy)-3-ethyl-2,5,6-trimethylbenzoic acid (1.51 mg, 1.85 pmol, 16 %) was obtained as a white powder pure by HNMR and LCMS. LCMS m / z = 815.2 [M-HJ-; 1H NMR (400 MHz, CDC13) 8 10.70 (s, 1H), 7.06 (s, 1H), 6.23 (t, J = 1.5 Hz, 1H), 5.67 (d, J = 1.4 Hz, 1H), 4.04 (s, 1H), 3.80 (s, 3H), 2.88 (s, 3H), 2.60 (s, 3H), 2.48 (d, J = 8.5 Hz, 7H), 2.40 - 2.27 (m, 4H), 2.25 (s, 3H), 2.12 (d, J = 21.8 Hz, 3H), 1.99 (s, 3H), 1.88 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H). Step-4a: Synthesis of 4-(2-ethyl-4-((methoxymethoxy)carbonyl)-3,5,6-trimethylphenoxy)-2,5,8-trimethylquinazolin-7-yl (R)-2-hy droxy-4-(( l-hydroxy-2-methoxy-6-methy 1-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-3,5,6-trimethylbenzoate Rr MeO^^^O (R)-3-bromo-4-((l -hydroxy -2-methoxy-6-methyl-4-oxocy cl ohexa-2,5-di ene-1-carbonyl)oxy)-2,5,6-trimethylbenzoic acid (24 mg, 1.2 Eq, 55 pmol) was dissolved in dry DCM (1 mL) and triethylamine (23 mg, 32 pL, 5 Eq, 0.23 mmol) and BOP-CI (14 mg, 1.2 Eq, 55 pmol) were sequentially added. The mixture was stirred at RT for 2h, and a solution of methoxymethyl 3-ethyl-4-((7-hydroxy-2,5,8-trimethylquinazolin-4-yl)oxy)-2,5,6-trimethylbenzoate (20 mg. 1 Eq. 46 pmol) in DCM (0.5 mL) was slowly added, followed by DMAP (0.56 mg, 0.1 Eq, 4.6 pmol). The obtained suspension was stirred for 14h at RT. After completion was observed, the reaction mixture was quenched with water and citric acid (saturated aqueous solution) was added. The aqueous phase was extracted 3 times with DCM, and the combined organic phase was washed with brine. The organic phase was then dried over sodium sulfate, filtered, evaporated and the resulting crude was then purified by column chromatography to provide the desired product 4-(2-ethyl-4-((methoxymethoxy)carbonyl)-3,5,6-trimethylphenoxy)-2,5,8-trimethylquinazolin-7-yl (R)-3-bromo-4-((l-hydroxy-2- methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2,5,6-trimethylbenzoate (30 mg, 35 pmol, 77 %) 1H NMR (400 MHz. CDC13) 8 7.21 (s, 1H), 6.29 (t, J = 1.6 Hz, 1H). 5.73 (d, J = 1.4 Hz. 1H). 5.52 (s, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 2.96 (s, 3H), 2.62 (s, 3H), 2.60 (s, 3H), 2.59 - 2.51 (m, 4H), 2.47 - 2.37 (m, 4H), 2.23 - 2.14 (m, 3H), 2.07 (s, 3H), 1.95 (s, 3H), 1.02 (t, J = 7.5 Hz. 3H). Step-5a: Synthesis of (R)-4-((7-((3-bromo-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocy clohexa-2.5-diene-l-carbonyl)oxy)-2.5.6-trimethylbenzoyl)oxy )-2.5.8-trimethylquinazolin-4-yl)oxy)-3-ethyl-2,5,6-trimethylbenzoic acid = Example 17. Rr MeCT^O 4-(2-ethyl-4-((methoxymethoxy)carbonyl)-3,5,6-trimethylphenoxy)-2,5,8- trimethylquinazolin-7-yl (R)-3-bromo-4-(( 1 -hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2,5,6-trimethylbenzoate (10 mg, 1 Eq, 12 pmol) was dissolved in DCM (1.0 mL), and HC1 (8.5 mg, 77 pL, 3 molar, 20 Eq, 0.23 mmol)) (3M in CPME) was added, and the mixture was stirred 16h at RT. The reaction mixture was then evaporated under reduced pressure, the residue was purified ovser silica gel column chromatography. After lyophilization, (R)-4-((7-((3-bromo-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-2,5,6-trimethylbenzoyl)oxy)-2,5,8-trimethylquinazolin-4-yl)oxy)-3-ethyl-2,5,6-trimethylbenzoic acid (2.29 mg, 2.81 pmol, 24 %) was obtained as a white powder pure by HNMR and LCMS. LCMS m / z = 813.2 [M-H]-; 1HNMR (400 MHz. CDC13) 5 10.70 (s, 1H), 7.06 (s, 1H), 6.23 (t, J = 1.5 Hz, 1H), 5.67 (d, J = 1.4 Hz. 1H), 4.04 (s, 1H), 3.80 (s, 3H), 2.88 (s, 3H). 2.60 (s, 3H). 2.48 (d, J = 8.5 Hz, 7H), 2.40 - 2.27 (m, 4H), 2.25 (s, 3H), 2.12 (d, J = 21.8 Hz, 3H), 1.99 (s, 3H), 1.88 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H). Synthesis of Example 19: PmBx5^QEt 1 Equiv. Pd(PPh3)4 (10 mol %) K2CO3 (3 Equiv.) Methyl (E)-4-(benzyloxy)-2-(2-ethoxyvinyl)-5-fluoro-3,6-dimethylbenzoate In a microwave vial, (trans)-1-Ethoxyethene-2-boronic acid pinacol ester (544.7 mg, 583 pL, 1.2 Eq, 2.750 mmol), methyl 4-(benzyloxy)-3-fluoro-2,5-dimethyl-6-(((trifluoromethyl)sulfonyl)oxy)benzoate (1000 mg, 1 Eq, 2.292 mmol), K2CO3 (950.1 mg, 3 Eq, 6.875 mmol) and tetrakis (264.8 mg, 0.1 Eq, 229.2 pmol) were dissolved on 1,4-Dioxane (18 rnL) and water (2.0 mL). nitrogen was bubbled through the solution for 10 min. Then, the mixture was heated to 70 °C for 1 h. The reaction was quenched by the addition of aq. sat. NaHCOs and extracted with Et20 (3 x 20 mL). The combined organic layers were washed with brine and dried over MgSO4. After evaporation of the solvent under reduced pressure, the residue was purified by FC on SiO2 0 to 20 % EtOAc in CyH to afford the desired product as a colourless solid (820 mg, 99 %). ‘HNMR (400 MHz. CDCh) 5 7.53 - 7.29 (m, 5H). 6.39 (d. J= 13.0 Hz. 1H), 5.67 (d, J = 13.0 Hz, 1H), 5.01 (s, 2H), 3.85 (m, 4H), 2.20 (d, J= 2.4 Hz, 3H), 2.13 (s, 3H), 1.32 (t, J= 7.0 Hz, 3H). Methyl 4-(benzyloxy)-3-fluoro-2,5-dimethyl-6-(2-oxoethyl)benzoate Methyl (E)-4-(benzyloxy)-2-(2-ethoxyvinyl)-5-fluoro-3,6-dimethylbenzoate (840 mg, 1 Eq, 2.34 mmol) was dissolved in HC1 (171 mg, 4.69 mL, 1 molar, 2 Eq, 4.69 mmol) and stirred for 16 h. The solvent was removed and the cured material used without further purification. LC-MS: m / z = 331.1 [M+H]+ 6-(benzyloxy)-7-fluoro-5,8-dimethylisoquinolin-l(2H)-one In a vial methyl (E)-4-(benzyloxy)-3-fluoro-6-(2-hydroxyvinyl)-2,5-dimethylbenzoate (773 mg, 1 Eq, 2.34 mmol) was dissolved in acetic acid (5 g, 5 mL, 40Eq, 0.09 mol) then ammonia (3 g, 4 mL, 25% Wt, 20 Eq, 0.05 mol) was added and the solution was heated to 60 °C for 16h. The volatiles were removed and the residue purified by FC on SiO2 0 to 30 % EtOAc in CyH afford the pure product as a colourless solid (148 mg, 498 pmol, 21.3 %). LC-MS m / z= 298.1 [M+H]+ 6-(benzyloxy)-l-chloro-7-fluoro-5,8-dimethylisoquinoline 6-(benzyloxy)-7-fluoro-5,8-dimethylisoquinolin-l(2H)-one (148 mg, 1 Eq, 498 pmol) was refluxed in Phosphorus oxychloride (2 g, 1 mL, 20 Eq, 0.01 mol) for 2h. then the Volatiles was removed and the residue azeotroped with PhMe (2 mL) twice. The residue was dissolved in EtOAc and washed with NaHCO? and brine. The organic layer was dried over MgSO4 and the solvent was reduced under reduced pressure. The residue was purified by FC on SiO2 0 to 30 % EtOAc in CyH to afford the product as a brown solid (111 mg, 352 pmol, 70.6 %). 'll NMR (400 MHz, CDCh) 5 8.18 (d, J = 5.7 Hz, 1H), 7.60 (d, J= 5.7 Hz, 1H), 7.47 - 7.34 (m. 5H), 5.13 (s, 2H), 2.92 (d, J= 3.1 Hz, 3H), 2.43 (s, 3H). Methoxymethyl 4-((6-(benzyloxy)-7-fhioro-5,8-dimethylisoquinolin- l-yl)oxy)-2,3,5,6-tetramethylbenzoate To 6-(benzyloxy)-l-chloro-5,8-dimethylisoquinoline (50 mg, 1 Eq, 0.17 mmol) and methoxymethyl 4-hydroxy-2,3,5,6-tetramethylbenzoate (44 mg, 1.1 Eq, 0.18 mmol) inNMP (1 mL) was added CS2CO3 (60 mg, 1.1 Eq, 0.18 mmol) and stirred for 16 h at 100 °C. The reaction was quenched by the addition of aq. sat. NH4CI and the aqueous phase was extracted with EtOAC (3x 15 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed and the residue used without further purification. LC-MS: m / z = 474.1 [M-C2H4O+H]+ Methoxymethyl 4-((6-hydroxy-5,8-dimethylisoquinolin-l-yl)oxy)-2,3,5,6-tetramethylbenzoate To a solution of methoxymethyl 4-((6-(benzyloxy)-5,8-dimethylisoquinolin-l -yl)oxy)-2,3,5.6-tetramethylbenzoate (85 mg, 1 Eq, 0.17 mmol) in THF (5 mL) was added Pd / C (18 mg, 0.1 Eq. 17 pmol, 10 wt. %) and the mixture was allowed to stir at room temperature for 2 h. Then, the mixture was filtered through a pad of Celite (R) and the solvent was removed under reduced pressure. The residue purified bx FC on SiCh 0 to 40 % EtOAc in CyH, to afford the desired product as a colorless solid ((10 mg, 23 pmol, 14 % over 2 steps). LC / MS: m / z = 427.1 7-fluoro-l-(4-((methoxymethoxy)carbonyl)-2,355,6-tetramethylphenoxy)-5,8- dimethylisoquinolin-6-yl (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4- oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoate To a suspension of (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoic acid (13 mg, 1.3 Eq, 30 pmol) and methoxymethyl 4-((7-fluoro-6-hydroxy-5,8-dimethylisoquinolin-l-yl)oxy)-2,3,5,6-tetramethylbenzoate (10 mg. 1 Eq. 23 pmol) in DCM (0.5 mL) was added a solution of EDC (5.8 mg, 1.3 Eq, 30 pmol) in DCM (0.1 mL) over 1 h via syringe pump. The mixture was stirred for 2 h. Then, the reaction was quenched by the addition of NH4CI. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic phases were washed with 10 % aq. citric acid, brine and dried over MgSO4. The solvent was evaporated and the residue purified by FC on S1O2 0 to 50 % EtOAc in CyH to afford the pure product. (9.4 mg, 11 pmol, 47 %). 'HNMR (400 MHz, CDCh) 5 7.90 (d, J= 6.0 Hz, 1H), 131 (d, J= 6.0 Hz, 1H), 6.27 (t, J= 1.5 Hz, 1H), 5.71 (d, J = 1.4 Hz, 1H), 5.46 (s, 2H), 3.84 (s, 3H), 3.55 (s, 3H), 2.90 (d, J =2.1 Hz. 3H), 2.62 (s, 3H), 2.49 (s, 3H), 2.25 (s, 6H), 2.02 (s, 6H). (R)-4-((6-((3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene- l-carbonyl)oxy)-5,6-dimethylbenzoyl)oxy)-7-fluoro-5,8-dimethylisoquinolin-l-yl)oxy)-2,3,5,6-tetramethylbenzoic acid (Example 19) 7-fluoro-l-(4-((methoxymethoxy)carbonyl)-2,3,5,6-tetramethylphenoxy)-5,8-dimethylisoquinolin-6-yl (R)-3-bromo-2-hydroxy-4-((l-hydroxy-2-methoxy-6-methyl-4-oxocyclohexa-2,5-diene-l-carbonyl)oxy)-5,6-dimethylbenzoate (9.4 mg, 1 Eq, 11 pmol) was treated with HC1 (2 mL, 4 molar in 1,4-dioxane) for 2 h. Then, the solvent was evaporated and the residue purified by prep HPLC (H2O / MeCN) to afford the pure product (5.3 mg, 6.6 pmol, 59 %). LC-MS: m / z = 804.1 [M-H]' 1HNMR (400 MHz, MeOD) 5 7.78 (d, J = 6.3 Hz, 1H), 7.53 (d, J = 6.1 Hz, 1H), 6.28 - 6.18 (m, 1H), 5.75 (s, 1H), 3.91 (s, 3H), 2.94 (d, J = 2.7 Hz, 3H), 2.65 (s, 3H), 2.45 (s. 3H), 2.28 (s, 6H). 2.20 (s, 3H). 2.08 (s. 3H). 2.03 (s. 6H). Other examples can be prepared according to the description of the procedure used for Example 19 by exchanging the respective reagents and precursors. Fluorogenic peptide detection of Calcineurin phosphatase activity Calcineurin dephosphorylates the fluorogenic peptide AQT0670 (AssayQuant) in a time-dependent process. Calcineurin is a heterodimeric enzyme of Calcineurin A and B subunits. Both the alpha(a) and beta(P) isoforms of Calcineurin A were tested in the following assay. By combining calcineurin, calmodulin, and AQT0670, the fluorescent signal will decrease over time and the measured slope can be determined and normalized for activity. Specifically, test and control compounds were 2X serially diluted in a 12-point dose curve in the 96-well compound plates (top final concentrations varying from 1 to 80 pM), and 1 pL was added in duplicate side by side into the black polystyrene 384 well plates with a nonbinding surface (Coming, cat# 3575). 2X Stocks of enzyme, substrate / calmodulin and substrate were prepared in assay buffer (25 mM HEPES, pH 7.5, 100 mM NaCl, 1.5 mM CaCh, 6 mM MgCb, 0.01% Tween-20, 1 mM TCEP) such that the final concentrations in the assay were as follows in 25 pL reaction volume: Isoform Calcineurin (nM) Calmodulin (nM) AQT0670 (pM) a Isoform 10 5 10 P Isoform 10 5 10 First, 2X enzyme solutions were aliquoted to the corresponding wells on the assay plate. Assays for the a isoform had 2X enzyme solutions in all wells except for the 100% inhibition wells that only had buffer added, and the assay was begun with the addition of 2X substrate / calmodulin to all wells. For P isoform assays, 2X enzyme solutions were added to all wells, and the assay was begun with addition of 2X substrate / calmodulin to all wells other than the 100% inhibition wells where only 2X substrate was added. After reaction initiation, the fluorescence intensity is measured continuously for 1.5 hours exciting at 360 nm and monitoring emission at 485 nm on a BMG CLARIOstar microplate reader at room temperature. Slope values (change in fluorescence intensity / min) were determined over the linear portion of curve for each well using the kinetic calculation function of the MARS data analysis software (BMG LabTech) for all samples. The inhibitor dose response curves were analyzed using a normalized ICso regression curve fitting model (4 parameters) with control-based normalization. The IC50 results were provided in Table 3. Table 3. Fluorogenic Peptide Phosphatase Mean Compound No. hPPP3CB IC50 (pM) Compound No. hPPP3CB IC50 (pM) Compound No. hPPP3CB IC50 (pM) 1 0.060 2 0.059 3 0.058 4 0.151 5 2.563 6 1.262 7 3.378 8 4.950 9 0.025 10 11.007 11 80.000 12 0.770 13 3.960 14 1,012 17 1.450 19 0.011 NFAT-Luciferase Reporter Assay The following protocol is a luciferase-based reporter assay to measure inhibition of nuclear factor of activated T-cells (NFAT) in cellular lysates mediated by calcineurin inhibitors. Jurkat Tcells, engineered with a luciferase reporter controlled by NFAT-response elements were used in this assay. When stimulated with calcium ionophores or Tcell receptor (TCR) stimulants. Calcineurin dephosphorylates NF AT which then translocates to the nucleus. Activated nuclear NF AT binds the NFAT-response elements and induces transcription of the luciferase signal. Percent inhibition in this assay was measured by the reduction of the luciferase signal. Cell line NF AT Reporter (Luc)-Jurkat Recombinant Cell Line (BPS BioScience, 60621). Buffer Components RPMI Cell culture media=RPMI-1620 (ATCC-30-2001) + 10% FBS (ATCC 30-2020) + 2mM L-Glutamine (ATCC 30-2214); (RPMI = Roswell Park Memorial Institute, FBS = fetal bovine serum). G418 = Geneticin Selective Antibiotic (G418 Sulfate) (1 mg / mL final concentration) (Thermo Fisher, 10131035). Assay Reagents DMSO (Hybri-max (Sigma D2650, 5 x 5mL ampules) ONE-Step luciferase assay system (BPS, 60690) Phorbol 12-myristate 13-acetate (PMA, Sigma, P8139) lonomycin (Sigma, 11957). Procedure NF AT Reporter (Luc) Jurkat Recombinant Cell Line stocks were maintained in RPMI media containing Img / mL G418. 24-48h prior to assay, cells were washed and resuspended in RPMI without G418. Cells were plated into an assay plate at 0.5-0.7xl06 cells / well in 40 pL RPMI media in a 96 well plate on the day of assay. Test compounds were reconstitued in DMSO and serially diluted to desired concentrations (3-fold, 9-point dose response), and 5 pL of each was added to the cells in the assay plate. PMA and lonomycin were added to cells at a final concentration of 18.5ng / mL and 750 ng / mL, respectively. Treated cells were incubated at 37 °C, 5% CO2 for 4h. Upon completion of incubation, the assay plate was equilibrated to room temperature for approximately 20 min. ONE-Step Luciferase Assay system was added (1:1 by volume) to each well, and the plate was incubated on plate shaker for 10 min at room temperature. The sample luminescence was measured using a CLARIOstar Plate Reader. Data Analysis Data analysis were normalized by calculating the percent response / inhibition for each of the sample values with 100% inhibition defined as the Cyclosporin treated control and 0% inhibition as the DMSO vehicle control. The data points for each compound are fit to a 4PL dose-response curve. The calculated ICso data are disclosed in Table 4. Table 4. Jurkat NF AT Reporter Assay Mean Compound No. Jurkat NFAT IC50 (pM) Compound No. Jurkat NFAT ICso (pM) Compound No. Jurkat NFAT ICso (pM) 1 0.0014 2 0.0046 3 0.0100 4 0.0102 5 0.0158 6 0.0190 7 0.0292 8 0.0361 9 0.1199 10 0.2124 11 0.3126 12 - 13 - 14 - Rat Whole Blood IL-2 Secretion Assay The following protocol measures the secreted protein levels of IL-2 in ex vivo mitogen stimulated rat whole blood and response / inhibition assessed with calcineurin inhibitor treatment. Inhibition of calcineurin impedes dephosphorylation of its substrate, NF AT preventing nuclear localization thereby blocking expression of cytokine genes like IL-2, necessary for T-cell activation. Percent inhibition of IL-2 was quantified by the reduction of the IL-2 levels using ELISA based methods on treated whole blood supernatants. Primary cells: Rat whole blood, ~7-8 week old male Wistar Han. BioIVT. Cell culture Reagents: RPMI 1640; high glucose, ATCC Catalog# 30-2001 lx DPBS, Coming Catalog# 21-031-CV DMSO: Hybri-max, Sigma D2650, 5 x 5mL ampules. Other reagents: Concanavalin A (ConA). MP Catalog# 150710 Rat IL-2 Quantikine ELISA, R&D Biosciences, Catalog #R2000. Procedure Whole blood volume of 190ul were dispensed into each well of 96 well plate and stimulated ex vivo with Concanavalin A (20pg / ml) with the addition of vehicle (DMSO) or test compounds. Test compounds were reconstitued in DMSO and serially diluted (4-fold, 12-point dose response), to desired concentrations and incubated at 37 °C, 5% CO2. Supernatants were harvested after 24 hours following centrifugation for 15min at 2200Xg at RT. Supernatants were diluted and tested for IL-2 protein levels following manufacturer’s instructions (Rat IL-2 Quantikine ELISA, R&D Biosciences, Catalog #R2000). Samples were measured at 450 & 570nm using the CLARIOstar Plate Reader within 30min of addition of stop solution. Subtract 570 nm reading from 450 nm as the wavelength corrected values to use for analysis. Data Analysis The data were normalized by calculating percent inhibition for each of the sample values with 100% inhibition defined as the unstimulated plate control and 0% inhibition as stimulated plate control. The data points for each compound are fit to a 4PL dose-response curve. The calculated IC50 data are disclosed in Table 5. Table 5. Whole Blood Assay Mean Compound No. Whole blood IC50 (pM) Compound No. Whole blood IC50 (pM) Compound No. Whole blood IC50 (pM) 1 0.225 2 3.094 3 6.700 4 6.665 5 0.849 6 0.253 7 2.688 8 2.220 9 7.660 10 17.845 11 - 12 - 13 0.643 14 0.068 While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

1. A compound represented by Formula (I):Formula(I)or a pharmaceutically acceptable salt, a stereoisomer and a mixture of stereoisomers, or a prodrug thereof;wherein each Ri, R2, and R3 is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(O)Ra, and C(O)NRbRc;R4 is selected from absent, H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(O)Ra, and C(O)NRbRc;each Ra, Rb, and Re is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or Rb and Rc can be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring;Rs and Re together form a substituted or unsubstituted a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; wherein the substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally fused or optionally bridged;Xi and X2 are each independently selected from -0- or -NRb-, wherein preferably Rb is H, D, a substituted or unsubstituted C1-6 alkyl;Yi and Y2 are independently selected from CH and N, provided that at least one of Yi and Y2 is N;m is 0, 1, 2, 3, 4, or 5;n is 0, 1, 2, or 3; and0 is 0, 1, 2, 3. or 4.

2. The compound of claim 1, wherein both Y1 and Y2 are N; wherein each Ri, R2, and R3 is independently selected from H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl. ORa. CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SO3Ra, COORa, C(O)Ra, and C(O)NRbRc;3. The compound of claim 1 or claim 2, wherein Xi and X2 are both -0-, or Xi and X2 are both -NH, or one of Xi and X2 is -O- and the other is -NH-.

4. The compound of any one of the preceding claims, wherein Xi and X2 are both -0-.

5. The compound of any one of the preceding claims, wherein m is 3, 4. or 5.

6. The compound of any one of the preceding claims, wherein n is 1 or 2.

7. The compound of any one of the preceding claims, wherein 0 is 3 or 4.

8. The compound of any one of the preceding claims, wherein each Ri, R2, and R3 is independently selected from a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted -O-C1-6 alkyl, OH, F, Cl, Br, -CN, -CONHRb, -COORa; wherein each Ra isindependently H or a substituted or unsubstituted Ci-6 alky l, each Rb is independently H, OH, or a substituted or unsubstituted Ci-6 alkyl.

9. The compound of any one of the preceding claims, wherein each Ri is independently F, Cl, Br, a substituted or unsubstituted C1-3 alkyl, a substituted or unsubstituted -O-C1-3 alkyl, or a substituted or unsubstituted -COO-C1-3 alkyl.

10. The compound of any one of the preceding claims, wherein at least one Ri is -COOH, and at least one Ri is a substituted or unsubstituted C1-3 alkyd (such as -CH3, -CF3, or -CH2CH3).

11. The compound of any one of the preceding claims, wherein each R2 and each R3 is independently selected from F, Cl, Br, OH, a -O-C1-3 alkyl such as -OCH3, and a substituted or unsubstituted C1-3 alky 1 such as -CH3, -CF3, or -CH2CH3.

12. The compound of any one of the preceding claims, wherein each R2 is a substituted or unsubstituted C1-3 alky 1 (such as -CH3, -CFs, or -CH2CH3).

13. The compound of any one of the preceding claims, wherein each R3 is independently F, CL Br. OH, -OCH3. or a substituted or unsubstituted C1-3 alkyl (such as -CH3, -CF3. or -CH2CH3).

14. The compound of any one of the preceding claims, wherein R4 is OH, -NH2, F, Cl, a substituted or unsubstituted C1-6 alkyl (preferably. -CH3 or -CH2CH3).

15. The compound of claim 1, wherein the compound is further represented by Formula (IV) or Formula (VI):Formula (VI);wherein R7 is H, D, or a substituted or unsubstituted alkyl (preferably a substituted or unsubstituted C1-6 alkyl);Rs is H. D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ORa, CN, NRbRc, NRaC(0)Ra, S(O)Ra, S(O)2Ra, SO2NRbRc, SOsRa, COORa, C(O)Ra, and C(O)NRbRc; andp is 0, 1, 2, 3, or 4.

16. The compound of claim 15, wherein p is 2.

17. The compound of claim 15 or 16, wherein each Rs is independently selected from a substituted or unsubstituted C1-3 alkyl, and a substituted or unsubstituted -O-C1-3 alkyl.

18. The compound of claim 1, wherein the compound is any one of those compounds in Table 1.

19. A pharmaceutical composition comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. The composition of claim 19, wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration.

21. A method for treating an inflammatory-related disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the compound of any one of claims 1-18.

22. The method of claim 21, wherein the inflammatory-related disease or disorder is a systemic inflammatory-related disease or disorder.

23. The method of claim 21, wherein the inflammatory-related disease or disorder is a pulmonary condition.

24. The method of claim 23, wherein the compound is administered to the subject via inhalation.

25. The method of claim 21, wherein the inflammatory-related disease or disorder is selected from the group consisting of allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary' disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, and respiratory tract inflammation.

26. The method of claim 21, wherein the inflammatory-related disease or disorder is a skin condition.

27. The method of claim 21, wherein the inflammatory-related disease or disorder isselected from the group consisting of psoriasis, dermatitis, eczema, and hives.

28. The method of claim 21, wherein the inflammatory-related disease or disorder ispsoriasis.

29. The method of claim 28, wherein psoriasis is selected from the group consisting ofplaque psoriasis, flexural psoriasis (inverse psoriasis), guttate psoriasis, pustular psoriasis, nail psoriasis, psoriatic arthritis, and erythrodermic psoriasis.

30. The method of claim 21. wherein the inflammatory-related disease or disorder isdermatitis.

31. The method of claim 30, wherein the dermatitis is selected from the group consistingof contact dermatitis, atopic dermatitis, nummular dermatitis, seborrheic dermatitis, and stasis dermatitis.

32. The method of claim 21, wherein the inflammatory-related disease or disorder is anocular disorder or disease.

33. The method of claim 32, wherein the ocular disorder or disease is selected from thegroup consisting of dry eye syndrome (DES), Sjogren's syndrome, uveitis, conjunctivitis (pink eye), keratitis, keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), autoimmune disorders of the ocular surface, including cicatrizing conjunctivitis, blepharitis, and scleritis.

34. A method of inhibiting calcineurin, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-18.

35. A method of preventing organ transplant rejection in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-18.

36. A method of treating fungal infection in a subject in need thereof, comprising topically administering to the subject a therapeutically effective amount of the compound of any one of claims 1-18.

37. A method of protecting a kidney by reducing immunosuppression-induced nephrotoxicity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-18.

38. A method of treating a condition or disorder associated with abnormal Calcineurin activity in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of any one of claims 1-18.

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